Bicyclic methylene aziridines and reactions thereof

ABSTRACT

The oxidative functionalization of olefins is a common method for the formation of vicinal carbon-heteroatom bonds. However, oxidative methods to transform allenes into synthetic motifs containing three contiguous carbon-heteroatom bonds are much less developed. The use of bicyclic methylene aziridines (MAs), prepared via intramolecular allene aziridination, as scaffolds for functionalization of all three allene carbons, among other reactions, is described herein.

RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §119(e) to U.S.Provisional Patent Application No. 61/528,596, filed Aug. 29, 2011,which is incorporated herein by reference.

BACKGROUND OF THE INVENTION

Many pharmaceuticals and other biologically active molecules containsequences of at least three contiguous heteroatom-bearing carbons(triads). Important examples compounds that include such triads includeTamiflu® (oseltamivir phosphate) and Relenza® (zanamivir).

Molecules containing sequences of at least three contiguousheteroatom-bearing carbons are difficult to prepare, while syntheticmethods for preparing two continuous heteroatom-bearing carbons are muchfurther developed. Olefins are popular substrates for a host ofoxidative transformations designed to introduce new C—N bonds intomolecules. For example, the oxidative functionalization of olefins is acommon method for the formation of vicinal carbon-heteroatom bonds.However, motifs having three contiguous heteroatom-bearing carbons canbe difficult to prepare directly from simple hydrocarbon precursors,even reactive moieties such as olefins. Even more problematic is thatthe triads are difficult to prepare in enantioenriched form.

While much is known about the oxidative functionalization of olefins,considerably less is known about the oxidations of allenes, despite thepotential to efficiently generate three new contiguousheteroatom-bearing chiral centers. New methods for the oxidation ofallenes are therefore needed to add important flexibility to currentsynthetic methods. New methods for the preparation of synthetic motifscontaining three contiguous carbon-heteroatom are also needed, forexample, to provide more efficient syntheses of important biologicallyactive molecules.

Additionally, chiral N,N-aminals are structural motifs found in manypharmaceuticals and biologically active natural products, such as thepyrroloindoline alkaloids, the phakellin-type pyrrole-imidazolealkaloids, and the lycoposerramines, many of which exhibit promisingtherapeutic activity. However, there are very few methods for theefficient preparation of chiral N,N-aminals. Thus, new methods areneeded for the synthesis of N,N-aminals from readily available startingmaterials or intermediates.

SUMMARY

The invention provides efficient processes to prepare asymmetric,heteroatom-bearing stereotriads and tetrads via allene oxidation. Thesubstrates include easily accessible enantioenriched allenes and themethods provide for flexibility in the number and type of heteroatomsthat can be stereoselectively introduced into a hydrocarbon chain orring. The methods allow for the transfer of chirality from anenantioenriched allene to three new carbon-heteroatom bonds. Thesestereodefined heteroatom-bearing triads and tetrads can be incorporatedinto biologically active molecules, including modified aminoglycosidesand neuraminidase inhibitors.

Accordingly, the invention provides methods for forming a bicyclicmethylene aziridine by an intramolecular allene aziridination reaction.The substrate can be an allene tethered to an amino (—NH₂) group, andthe amino group can be separated from the proximal allene carbon byabout 3, 4, 5, or 6 atoms linearly. The methods can include combiningthe allene, a rhodium catalyst, a solvent, and an oxidant, to provide areaction mixture, thereby initiating an intramolecular alleneaziridination reaction, to provide a bicyclic methylene aziridine.

The methods can include contacting the bicyclic methylene aziridine witha nucleophile to provide a nucleophile-addition product, optionallyfurther reacting the nucleophile-addition product with an electrophileto provide an electrophile-addition product. The bicyclic methyleneaziridine can also be reacted with an electrophile to provide anelectrophile-addition product, and optionally further reacted with anucleophile.

Any product of a reaction described herein can be further oxidized,reduced (e.g., with a hydride reagent or in the presence of H₂ and ametal catalyst), or hydrolyzed to form other useful compounds andintermediates, for example, synthetic motifs containing three contiguouscarbon-heteroatom bonds.

The invention also provides methods for reacting a bicyclic methyleneaziridine with a nitrene equivalent, such as an N-aminophthalimide, inthe presence of an oxidant to provide an N,N-spiroaminal. TheN,N-spiroaminal can have, for example, four contiguous carbon-heteroatombonds in the form of a tricyclic 1,4-diazaspiro[2.2]pentane (DASP). TheDASP can be contacted with a nucleophile to provide a bicyclicring-opened nucleophile-addition product.

The invention further provides methods for forming a bicyclic N,N-aminalin a one pot reaction. The methods can include forming a bicyclicmethylene aziridine by an intramolecular allene aziridination reactionas described above, followed by combining the bicyclic methyleneaziridine with a nitrene equivalent in the presence of an oxidant toprovide an N,N-spiroaminal, such as a tricyclic1,4-diazaspiro[2.2]pentane (DASP). The N,N-spiroaminal can then bereacted with a nucleophile to provide a bicyclic ring-openednucleophile-addition product, which can be used to provide other usefulproducts.

The invention also provides novel compounds of the Formulas describedherein, and novel compounds prepared by the methods described herein,for example, a compound having three contiguous carbon-heteroatom bonds.The invention further provides compounds of the Formulas describedherein that are useful as intermediates for the synthesis of otheruseful compounds.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the specification and are includedto further demonstrate certain embodiments or various aspects of theinvention. In some instances, embodiments of the invention can be bestunderstood by referring to the accompanying drawings in combination withthe detailed description presented herein. The description andaccompanying drawings may highlight a certain specific example, or acertain aspect of the invention. However, one skilled in the art willunderstand that portions of the example or aspect may be used incombination with other examples or aspects of the invention describedelsewhere in the specification.

FIG. 1. Examples of carbamate nitrene precursors and products, accordingto some embodiments.

FIG. 2. Allene oxidation methods to form stereotriads and tetrads. Thereactions provide access to multiple stereoisomers containing the samesubstitution pattern resulting in varied product topologies. Thereactions illustrate the translation of axial chirality to three newcarbon-heteroatom bonds. The variables R¹, R², and R³ are as defined forFormula I herein. Nu⁻, E⁺, and H⁻ are any suitable nucleophile,electrophile, or hydride source, for example, as described herein. Pg isa nitrogen protecting group.

FIG. 3. X-ray crystal structure of DASP 10a.

FIG. 4. Natural products and biologically active molecules havingdensely functionalized amines bearing stereodefined heteroatom groupslocated adjacent to the chiral nitrogen-bearing carbon occur frequently;and bioactive molecules with complex N/O/O and N/O/N stereotriads.

FIG. 5. New methods for allene oxidation and synthetic targets, where R,R¹, and R² are each independently an optionally substituted R¹ asdescribed herein.

FIG. 6. Representative approaches to amine stereotriads where R, R¹, andR² are each independently an optionally substituted R¹ as describedherein, and the catalyst can be a Rh catalyst as described herein.

DETAILED DESCRIPTION

Asymmetric heteroatom-bearing stereotriads and tetrads can be preparedvia allene oxidation by the methods described herein. Functionalizationof olefins can efficiently provide two new carbon-heteroatom bonds, forexample, by epoxidation, aminohydroxylation, diamination, oraziridination. The useful nature of the reactions when applied toallenes is illustrated by the allene functionalizations generallyoutlined in Scheme 1 below, where three or four new carbon-heteroatombonds can be formed by allene oxidation.

The R group can be a variety of alkyl, aryl, heteroalkyl, heteroaryl, orcycloalkyl groups, with a variety of substitutions and heteroatomsreplacing various carbons in the groups. Particularly useful examplesinclude allenic carbamates or sulfamates. R¹, R², and R³ can be, forexample, as defined for one or more of the Formulas described herein.

Allenic carbamates or sulfamates can be treated with a Rh(II) catalystin the presence of an oxidant to form a highly strained bicyclicmethylene aziridine. This reactive intermediate can bediastereoselectively transformed into a variety of stereotriads using adiverse array of nucleophiles and electrophiles. Examples of usefulnucleophiles include amines, carboxylic acids, alcohols, thiols,selenides, azides, halogens, and carbon nucleophiles includingmalonates, electronic-rich aromatic rings, and R₂Mg where R can be R¹ asdefined herein below. Examples of useful electrophiles includeelectrophilic sulfur, peroxyacids, N-halosuccinimides, N-haloamines, andN-aminophthalimides. These new methods thus offer an efficient approachto transferring the axial chirality of an allene to three newcarbon-heteroatom bonds and a variety of useful substituents.

Advantages of the methods include the facile preparation of reactantsand intermediates from readily accessible allenes, the ability tointroduce a wide variety of functionality, the need for only mildreaction conditions, that useful electron-withdrawing groups can bepresent on the aziridine nitrogen to promote subsequent reactivity, theinherent ring strain in the aziridine that promotes facile ring opening,and a high degree of possible stereocontrol.

Allene Aziridination to Bicyclic Methylene Aziridine Scaffolds

The invention thus provides a method comprising forming a bicyclicmethylene aziridine by an intramolecular allene aziridination reaction.An allene group can be tethered to an amino (—NH₂) group, and the aminogroup can be separated from the proximal allene carbon by 3, 4, 5, or 6atoms linearly. The aziridine nitrogen of the bicyclic methyleneaziridine can be substituted by an electron-withdrawing group, such as acarbamate or sulphone. The allene can be mono-substituted,di-substituted, tri-substituted, or tetra-substituted. The allene canbe, for example, a compound of Formula I:

wherein

R¹, R², and R³ are each independently H, alkyl, cycloalkyl, aryl,heteroaryl, heterocycle, (alkyl)cycloalkyl, (alkyl)aryl,(alkyl)heteroaryl, or (alkyl)heterocycle;

n is 1, 2, or 3;

Y is —C(═O)— or —S(═O)₂—; and

each Z is independently —(CH₂)—, —(CHR¹)—, or —(C(R¹)₂)—.

The method can include combining the allene, a rhodium catalyst, asolvent, and an oxidant, to provide a reaction mixture, therebyinitiating an intramolecular allene aziridination reaction, to provide abicyclic methylene aziridine. The rhodium catalyst can be any Rh(II)catalyst that is effective to promote the intramolecular alleneaziridination. In some embodiments, the reaction proceeds in at least30% yield, at least 40% yield, at least 50% yield, at least 60% yield,at least 70% yield, or at least 80% yield. In some embodiments, therhodium catalyst is Rh₂(esp)₂ where esp isα,α,α′,α′-tetramethyl-1,3-benzenedipropionate, or Rh₂(TPA)₄ where TPA istriphenylacetate. Other suitable rhodium catalysts include dimericrhodium catalysts with bulky ester-based or amide-based ligands,although strongly electron-withdrawing esters are not suitable in someembodiments.

The oxidant can be, for example, any suitable and effective hypervalentiodide oxidant. Examples include, but are not limited to, PhIO,PhI(OAc)₂, PhI(OPiv)₂, or PhI(CN)OTf. One-electron oxidants such ascerium(III) sulfate or lead(IV) acetate may also be employed. Oxidationmay also be carried out using standard electrochemical methods.

The reaction mixture can also include a drying agent, such as molecularsieves (e.g., 3A or 4A), for example, when PhIO is used as the oxidant,to adsorb or absorb water generated in the reaction Alkaline earth metaloxides, such as magnesium oxide, can be used to neutralize acetic acidor pivalic acid generated when PhI(OAc)₂ or PhI(OPiv)₂ are used as theoxidants. The solvent can be any suitable solvent or combination ofsolvents that provide sufficient solubility of the allene reactant andthe reagents to enable the reaction to proceed. Examples of potentialsolvents include acetone, methylene chloride, dichloroethane,chloroform, isopropyl acetate, benzene, toluene, xylenes, acetonitrile,ether, tetrahydrofuran, and combinations thereof. One skilled in the artwill be able to readily determine which solvents are suitable andeffective based on solubility of reactants and reagents, and theefficiency of the reaction. The reactions can be typically run at roomtemperature (˜23° C.). Some reactions, however, may benefit frominitially reduced temperatures such as about −30° C. or about 0° C.Other reactions can be enhanced by elevated temperatures, such as about30° C., about 35° C., about 40° C., about 50° C., about 70° C., about90° C., about 100° C., or about 110° C.

An example of the intramolecular aziridination is shown below in Scheme2, where each R is independently an alkyl or aryl group, Nu⁻ is anucleophile as described herein, E⁺ is an electrophile as describedherein, H⁻ is a hydride reagent, and R¹M is an organometallic reagentsuch as a Grignard reagent, an alkyl lithium reagent, or analkylcuprate. The bicyclic methylene aziridine can then be allowed toreact with a nucleophile to provide a nucleophile-addition product suchas an enesulphone or an enecarbamate (as illustrated in Scheme 2).Alternatively, the bicyclic methylene aziridine can be allowed to reactwith an electrophile such as an epoxide, an N-halo-succinimide, or anitrene equivalent. Additional reactions that can be carried out onbicyclic methylene aziridines are shown in FIG. 2.

A nucleophile for addition to the bicyclic methylene aziridine can be,for example, a carboxylic acid or a carboxylate anion, a halide, analcohol in the presence of an acid such as a Lewis acid, a thiol in thepresence of a Lewis acid, a cyanide, a nitrile, an alkoxide, an azide, aselenium nucleophile such as benzeneselenol, and the like. In someembodiments, the carboxylic acid can be an optionally substituted(C₂-C₂₄)carboxylic acid; the halide can be and alkali metal halide orR′₃SiCl where each R′ is independently alkyl, aryl, alkoxy, or aryloxy;the alcohol can be a (C₁-C₂₄)alcohol; the thiol can be an alkylthiol oran arylthiol; the cyanide can be an alkali metal cyanide; and the azidecan be an alkali metal azide. The acid can be any suitable and effectiveacid, such as a Lewis acid, a mineral acid, or an organic acid. TheLewis acid can be, for example, Sc(OTf)₃, Bi(OTf)₃, BF₃.OEt₂, TiCl₄,Ti(OiPr)₄, InCl₃, In(OTf)₃, or a lanthanide triflate. Brønsted acids mayalso promote the reaction, including phosphoric acids, carboxylic acids(e.g., AcOH, BzOH), p-toluenesulfonic acid, MsOH, other sulfonic acids,and the like.

As discussed above, the bicyclic methylene aziridine can be anenecarbonate or an enesulphone. In one embodiment, the bicyclicmethylene aziridine is a compound of Formula II:

wherein

R¹ and R² are each independently H, alkyl, cycloalkyl, aryl, heteroaryl,heterocycle, (alkyl)cycloalkyl, (alkyl)aryl, (alkyl)heteroaryl, or(alkyl)heterocycle;

n is 0, 1, or 2;

Y is —C(═O)— or —S(═O)₂—; and

each Z is independently —(CH₂)—, —(CHR¹)—, or —(C(R¹)₂)—.

In various embodiments, the bicyclic methylene aziridine can be abicyclic methylene aziridine illustrated in FIG. 1, or a derivativethereof.

A nucleophile-addition product can be, for example, a compound ofFormula III:

wherein R¹ and R² are each independently H, alkyl, cycloalkyl, aryl,heteroaryl, heterocycle, (alkyl)cycloalkyl, (alkyl)aryl,(alkyl)heteroaryl, (alkyl)heterocycle, or azide;

n is 0 or 1;

the dotted lines represent optional double bonds where only one of thedouble bonds is present;

Y is —C(═O)— or —S(═O)₂—; and

R^(N) is acetoxy, chloroacetoxy, halo, cyano, alkoxy, thioalkyl, orthioaryl.

As shown in Scheme 2, a variety of further reactions can be carried outon the nucleophile-addition product. Such reactions include hydrolysisof acyloxy groups such as acetoxy groups or chloroacetoxy groups, toprovide a hydroxyl substituent.

Suitable electrophiles for addition to the bicyclic methylene aziridinesor their nucleophile-addition products include N-halosuccinimides andhydrides. The electrophile-addition products can then be reduced toprovide synthetic motifs containing three contiguous carbon-heteroatombonds. Alternatively, the bicyclic methylene aziridine or thenucleophile-addition product can be reacted with a nitrene equivalent,such as an N-aminophthalimide, in the presence of an oxidant to providean N,N-spiroaminal, as shown below in Scheme 3.

Nitrene sources for intermolecular aziridination includeN-aminobenzoxazole, N-aminoquinazolones, RONH₂ where R is alkyl asdescribed herein, and ArONH₂ or ArSO₂NH₂ where Ar is aryl as describedherein. Further examples of nitrene equivalents are described byAnderson et al., J. Chem. Soc. (C), 1970, 576-582; Atkinson, et al.,Chem. Soc., Perkin I, 1984, 1905-1912; and Atkinson, et al., J. Chem.Soc., Chem. Comm., 1981, 160-162.

The N,N-spiroaminal can have four contiguous carbon-heteroatom bonds inthe form of a tricyclic 1,4-diazaspiro[2.2]pentane (DASP). The DASP anda nucleophile can be combined to provide a bicyclic ring-openednucleophile-addition product. Suitable examples of nucleophiles arediscussed above. The products can then be subjected to further reactionconditions, including but not limited to oxidation, reduction (e.g.,with a hydride reagent or in the presence of H₂ and a metal catalyst),or hydrolysis, to form other useful compounds and intermediates.

The invention further provides a method for forming a bicyclic anN,N-aminal in a one-pot reaction. The method can include forming abicyclic methylene aziridine by an intramolecular allene aziridinationreaction as discussed above. The bicyclic methylene aziridine can thenbe contacted with a nitrene source, such as a nitrene equivalentdescribed above (e.g., N-aminophthalimide), in the presence of anoxidant to provide an N,N-spiroaminal. The N,N-spiroaminal can then becontacted with a nucleophile to provide a bicyclic ring openednucleophile-addition product, all in one pot without any work-up betweensteps.

Reactions of Bicyclic MAs to Stereotriads

The scope of the reactions of methylene aziridines, enecarbamates, andenesuphones is further illustrated below in Schemes 4 and 5.

Scheme 4 Reactions of Enecarbamates.

substrate E^(⊕) Nu product yield dr

NCS NaCNBH₃

92% >10:1 NBS NaCNBH₃

73%  10:1 NIS none

100% by NMR E:Z 1:5

none

58% 2:1

NaCNBH₃

 57%* >10:1

NBS NaCNBH₃

82% 1.1:1 *Based on recovered starting material.

Scheme 5 Reactions of Enesulfamates. substrate E^(⊕) Nu product yield dr

NBS

59% >10:1 NBS NaCNBH₃

65%  >5:1 NBS MeMgBr

49% 2.8:1

NBS NaCNBH₃

53% >10:1

AcOH then NBS NaCNBH₃

43% >10:1 MeOH then NBS NaCNBH₃

43% >10:1

For a typical reaction, the E configuration controls dr better than Zconfiguration. Also, a stronger reductants can help prevent hydrolysisof the intermediate iminium ion. Finally, the scope of nucleophiles thatopen the sulfamate-based MA include alcohols, halides, carboxylic acids,thiols and amines.

1,4-Diazaspiro[2.2]-pentanes (DASPs)

Examples of substrates and DASP products are further illustrated belowin Scheme 6.

Reactions on DASP compounds are further illustrated below in Schemes7-10.

Other methods to access highly substituted vicinal diamines are limitedin number and flexibility. The use of sulfamate nitrene precursorsexpands the scope of nucleophiles for regioselective DASP ring-opening.Stereocontrol of the reduction of the intermediate imine/iminium may becontrolled using chiral reducing agents.

DASPs can be thought of as aminal-protected ketone. Formal hydrolysis ofthis “ketone” yields 1,3-diamines with good stereocontrol.

Scheme 10. Preparation of 1,3-Diamines from DASPs.

entry substrate additives (equiv) conversion 1 A CeCl₃•7H₂O (1)  0% 2NiCl₂•6H₂O (1)  0% 3 Ti(O^(i)Pr)₄ (1)  0% 4 ZnCl₂ (1)  0% 5 Cu(OTf)₂ (1)<50% 6 InCl₃ (1) <50% 7 Sc(OTf)₃ (1) mixture 8 BF₃OEt₂ (1) 100% 9 TsOH(1) 100% 10 Bi(OTf)₃ (1)  96%^(a) 11 Bi(OTf)₃ (0.2) 100% 12 Bi(OTf)₃(0.05) 100% 13 B AcOH, then Bi(OTf)₃ (0.05)^(b) 100% 14 ClCH₂CO₂H, thenBi(OTf)₃  0%^(c) (0.05) 15 AcOH at 35° C., then Bi(OTf)₃ 100%^(d)(88%)^(a) (0.05) ^(a)Isolated yield. ^(b)40 h reaction time. ^(c)Theproduct was the ring-opened DASP. ^(d)12 h reaction time.

The 1,3-diamines derived from the DASPs can be obtained in high yieldand diastereoselectivity (dr>10:1 in all cases). Preliminary resultsshow that stereocontrolled reduction of the ketone, such as thoseillustrated in Scheme 11 below, can be achieved.

A specific example of the synthesis of a 1,3-diaminoketone is shown inScheme 12.

An example of a one-pot DASP formation reaction is illustrated in Scheme13.

General Synthetic Methods

The invention provides various compounds and synthetic intermediates asdescribed herein. The compounds can be prepared by any of the applicabletechniques described herein and they can be modified by a variety oforganic synthesis techniques to provide various substituted analogs andderivatives. Many such techniques are well known in the art. However,relevant techniques and transformations are also elaborated inCompendium of Organic Synthetic Methods (John Wiley & Sons, New York),Vol. 1, Ian T. Harrison and Shuyen Harrison, 1971; Vol. 2, Ian T.Harrison and Shuyen Harrison, 1974; Vol. 3, Louis S. Hegedus and LeroyWade, 1977; Vol. 4, Leroy G. Wade, Jr., 1980; Vol. 5, Leroy G. Wade,Jr., 1984; and Vol. 6; as well as standard organic reference texts suchas March's Advanced Organic Chemistry: Reactions, Mechanisms, andStructure, 5^(th) Ed. by M. B. Smith and J. March (John Wiley & Sons,New York, 2001); Comprehensive Organic Synthesis, Selectivity, Strategy& Efficiency in Modern Organic Chemistry, in 9 Volumes, Barry M. Trost,Editor-in-Chief (Pergamon Press, New York, 1993 printing); AdvancedOrganic Chemistry, Part B: Reactions and Synthesis, Second Edition, Caryand Sundberg (1983); Protecting Groups in Organic Synthesis, SecondEdition, Greene, T. W., and Wutz, P. G. M., John Wiley & Sons, New York;and Comprehensive Organic Transformations, Larock, R. C., SecondEdition, John Wiley & Sons, New York (1999).

DEFINITIONS

As used herein, the recited terms have the following meanings. All otherterms and phrases used in this specification have their ordinarymeanings as one of skill in the art would understand. Such ordinarymeanings may be obtained by reference to technical dictionaries, such asHawley's Condensed Chemical Dictionary 14^(th) Edition, by R. J. Lewis,John Wiley & Sons, New York, N.Y., 2001.

References in the specification to “one embodiment”, “an embodiment”,etc., indicate that the embodiment described may include a particularaspect, feature, structure, moiety, or characteristic, but not everyembodiment necessarily includes that aspect, feature, structure, moiety,or characteristic. Moreover, such phrases may, but do not necessarily,refer to the same embodiment referred to in other portions of thespecification. Further, when a particular aspect, feature, structure,moiety, or characteristic is described in connection with an embodiment,it is within the knowledge of one skilled in the art to affect orconnect such aspect, feature, structure, moiety, or characteristic withother embodiments, whether or not explicitly described.

The singular forms “a,” “an,” and “the” include plural reference unlessthe context clearly dictates otherwise. Thus, for example, a referenceto “a compound” includes a plurality of such compounds, so that acompound X includes a plurality of compounds X. It is further noted thatthe claims may be drafted to exclude any optional element. As such, thisstatement is intended to serve as antecedent basis for the use ofexclusive terminology, such as “solely,” “only,” and the like, inconnection with the recitation of claim elements or use of a “negative”limitation.

The term “and/or” means any one of the items, any combination of theitems, or all of the items with which this term is associated. Thephrase “one or more” is readily understood by one of skill in the art,particularly when read in context of its usage. For example, one or moresubstituents on a phenyl ring refers to one to five, or one to four, forexample if the phenyl ring is disubstituted.

The term “about” can refer to a variation of ±5%, ±10%, ±20%, or ±25% ofthe value specified. For example, “about 50” percent can in someembodiments carry a variation from 45 to 55 percent. For integer ranges,the term “about” can include one or two integers greater than and/orless than a recited integer at each end of the range. Unless indicatedotherwise herein, the term “about” is intended to include values, e.g.,weight percents, proximate to the recited range that are equivalent interms of the functionality of the individual ingredient, thecomposition, or the embodiment.

As will be understood by the skilled artisan, all numbers, includingthose expressing quantities of ingredients, properties such as molecularweight, reaction conditions, and so forth, are approximations and areunderstood as being optionally modified in all instances by the term“about.” These values can vary depending upon the desired propertiessought to be obtained by those skilled in the art utilizing theteachings of the descriptions herein. It is also understood that suchvalues inherently contain variability necessarily resulting from thestandard deviations found in their respective testing measurements.

As will be understood by one skilled in the art, for any and allpurposes, particularly in terms of providing a written description, allranges recited herein also encompass any and all possible sub-ranges andcombinations of sub-ranges thereof, as well as the individual valuesmaking up the range, particularly integer values. A recited range (e.g.,weight percents or carbon groups) includes each specific value, integer,decimal, or identity within the range. Any listed range can be easilyrecognized as sufficiently describing and enabling the same range beingbroken down into at least equal halves, thirds, quarters, fifths, ortenths. As a non-limiting example, each range discussed herein can bereadily broken down into a lower third, middle third and upper third,etc. As will also be understood by one skilled in the art, all languagesuch as “up to”, “at least”, “greater than”, “less than”, “more than”,“or more”, and the like, include the number recited and such terms referto ranges that can be subsequently broken down into sub-ranges asdiscussed above. In the same manner, all ratios recited herein alsoinclude all sub-ratios falling within the broader ratio. Accordingly,specific values recited for radicals, substituents, and ranges, are forillustration only; they do not exclude other defined values or othervalues within defined ranges for radicals and substituents.

One skilled in the art will also readily recognize that where membersare grouped together in a common manner, such as in a Markush group, theinvention encompasses not only the entire group listed as a whole, buteach member of the group individually and all possible subgroups of themain group. Additionally, for all purposes, the invention encompassesnot only the main group, but also the main group absent one or more ofthe group members. The invention therefore envisages the explicitexclusion of any one or more of members of a recited group. Accordingly,provisos may apply to any of the disclosed categories or embodimentswhereby any one or more of the recited elements, species, orembodiments, may be excluded from such categories or embodiments, forexample, as used in an explicit negative limitation.

The allene starting materials can include various carbon chains and ringstructures, optionally substituted with one or more substituents.Examples of many suitable chains and ring structures that can besubstituents on allenes and their substituents are described below.

The terms “halogen” and “halo”, and “halide” refer to fluoro, chloro,bromo, and iodo groups, typically used as organic substratesubstituents.

The term “alkyl” refers to a branched or unbranched carbon chain having,for example, about 1-20 carbon atoms, and often 1-12, 1-10, 1-8, 1-6, or1-4 carbons. Examples include, but are not limited to, methyl, ethyl,1-propyl, 2-propyl, 1-butyl, 2-methyl-1-propyl, 2-butyl,2-methyl-2-propyl (t-butyl), 1-pentyl, 2-pentyl, 3-pentyl,2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl,1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl,2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl, hexyl, octyl, decyl,dodecyl, and the like. The alkyl can be unsubstituted or substituted,for example, as described in the definition of the term “substituted”below.

The alkyl can also be optionally partially or fully unsaturated incertain embodiments. As such, the recitation of an alkyl groupoptionally includes both alkenyl and alkynyl groups. The alkyl can be amonovalent hydrocarbon radical, as described and exemplified above, orit can be a divalent hydrocarbon radical (i.e., an alkylene), forexample, that links to other groups. In some embodiments, certain alkylgroups can be excluded from a definition. For example, in someembodiments, methyl, ethyl, propyl, butyl, or a combination thereof, canbe excluded from a specific definition of alkyl in an embodiment.

The term “alkoxy” refers to the groups alkyl-O—, where alkyl is definedherein. Preferred alkoxy groups include, e.g., methoxy, ethoxy,n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy,n-hexoxy, 1,2-dimethylbutoxy, and the like. The alkoxy can beunsubstituted or substituted.

The term “alkenyl” refers to a monoradical branched or unbranchedpartially unsaturated hydrocarbon chain (i.e. a carbon-carbon, sp²double bond) preferably having from 2 to 10 carbon atoms, about 2 to 6carbon atoms, or about 2 to 4 carbon atoms. Examples include, but arenot limited to, ethylene or vinyl, allyl, cyclopentenyl, and 5-hexenyl.An alkenyl can be unsubstituted or substituted.

The term “alkynyl” refers to a monoradical branched or unbranchedhydrocarbon chain, having a point of complete unsaturation (i.e. acarbon-carbon, sp triple bond), typically having from 2 to 10 carbonatoms, about 2 to 6 carbon atoms, or about 2 to 4 carbon atoms. Thisterm is exemplified by groups such as ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, andthe like. An alkynyl can be unsubstituted or substituted.

An “alkylene” refers to a saturated, branched or straight chainhydrocarbon radical of 1-18 carbon atoms, and having two monovalentradical centers derived by the removal of two hydrogen atoms from thesame or two different carbon atoms of a parent alkane. Typical alkyleneradicals include, but are not limited to, methylene (—CH₂—) 1,2-ethyl(—CH₂CH₂—), 1,3-propyl (—CH₂CH₂CH₂—), 1,4-butyl (—CH₂CH₂CH₂CH₂—), andthe like. An alkylene can be unsubstituted or substituted.

The term “cycloalkyl” refers to cyclic alkyl groups of, for example, 3to about 12, 3 to about 10, 3 to about 8, about 4 to about 8, or 5-6,carbon atoms having a single cyclic ring or multiple condensed rings.Cycloalkyl groups include, by way of example, single ring structuressuch as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like,or multiple ring structures such as adamantyl, and the like. Thecycloalkyl can be unsubstituted or substituted. The cycloalkyl group canbe monovalent or divalent, and can be optionally substituted asdescribed for alkyl groups. The cycloalkyl group can optionally includeone or more cites of unsaturation, for example, the cycloalkyl group caninclude one or more carbon-carbon double bonds, such as, for example,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, and the like.

As used herein, “aryl” refers to an aromatic hydrocarbon group derivedfrom the removal of one hydrogen atom from a single carbon atom of aparent aromatic ring system. The radical attachment site can be at asaturated or unsaturated carbon atom of the parent ring system. The arylgroup can have from 6 to about 20 carbon atoms. The aryl group can havea single ring (e.g., phenyl) or multiple condensed (fused) rings,wherein at least one ring is aromatic (e.g., naphthyl,dihydrophenanthrenyl, fluorenyl, or anthryl). Typical aryl groupsinclude, but are not limited to, radicals derived from benzene,naphthalene, anthracene, biphenyl, and the like. The aryl can beunsubstituted or optionally substituted, as described for alkyl groups.

The term “heteroaryl” refers to a monocyclic, bicyclic, or tricyclicring system containing one, two, or three aromatic rings and containingat least one nitrogen, oxygen, or sulfur atom in an aromatic ring, andthat can be unsubstituted or substituted, for example, with one or more,and in particular one to three, substituents, as described in thedefinition of “substituted”. Typical heteroaryl groups contain 2-20carbon atoms in addition to the one or more hetoeroatoms. Examples ofheteroaryl groups include, but are not limited to, 2H-pyrrolyl,3H-indolyl, 4H-quinolizinyl, acridinyl, benzo[b]thienyl, benzothiazolyl,β-carbolinyl, carbazolyl, chromenyl, cinnolinyl, dibenzo[b,d]furanyl,furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolisinyl,indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl,isoxazolyl, naphthyridinyl, oxazolyl, perimidinyl, phenanthridinyl,phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl,pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl,pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl, tetrazolyl,and xanthenyl. In one embodiment the term “heteroaryl” denotes amonocyclic aromatic ring containing five or six ring atoms containingcarbon and 1, 2, 3, or 4 heteroatoms independently selected fromnon-peroxide oxygen, sulfur, and N(Z) wherein Z is absent or is H, O,alkyl, aryl, or —(C₁-C₆)alkylaryl. In some embodiments, heteroaryldenotes an ortho-fused bicyclic heterocycle of about eight to ten ringatoms derived therefrom, particularly a benz-derivative or one derivedby fusing a propylene, trimethylene, or tetramethylene diradicalthereto.

The term “heterocycle” refers to a saturated or partially unsaturatedring system, containing at least one heteroatom selected from the groupoxygen, nitrogen, silicon, and sulfur, and optionally substituted withone or more groups as defined for the term “substituted”. A heterocyclecan be a monocyclic, bicyclic, or tricyclic group. A heterocycle groupalso can contain an oxo group (═O) or a thioxo (═S) group attached tothe ring. Non-limiting examples of heterocycle groups include1,3-dihydrobenzofuran, 1,3-dioxolane, 1,4-dioxane, 1,4-dithiane,2H-pyran, 2-pyrazoline, 4H-pyran, chromanyl, imidazolidinyl,imidazolinyl, indolinyl, isochromanyl, isoindolinyl, morpholinyl,piperazinyl, piperidinyl, pyrazolidinyl, pyrazolinyl, pyrrolidine,pyrroline, quinuclidine, tetrahydrofuranyl, and thiomorpholine, wherethe point of attachment can be at any atom accessible by known syntheticmethods.

When an aryl, heteroaryl, heterocycle, or cycloalkyl group is asubstituent, the group can be linked to the substrate via an alkylenegroup, thereby providing (alkyl)aryl, (alkyl)heteroaryl,(alkyl)heterocycle, or (alkyl)cycloalkyl substituents.

The terms “acyl” and “alkanoyl” refer to groups of the formula —C(═O)R,where R is an alkyl group as previously defined. The term “aroyl” refersto groups of the formula —C(═O)Ar, where Ar is an aryl group aspreviously defined.

The term “alkoxycarbonyl” refers to groups of the formula —C(═O)OR,where R is an alkyl group as previously defined.

The term “acyloxy” refers to groups of the formula —O—C(═O)R, where R isan alkyl group as previously defined. Examples of acyloxy groups includeacetoxy and propanyloxy.

The term “amino” refers to —NH₂, and the term “alkylamino” refers to—NR₂, wherein at least one R is alkyl and the second R is alkyl orhydrogen. The term “acylamino” refers to RC(═O)NH—, wherein R is alkylor aryl.

The term “protecting group” or “PG” refers to group that, when bound toa functional group, prevents undesired reactions from occurring at thefunctional group and that can be removed by conventional chemical orenzymatic steps to reestablish the original functional group. Theparticular removable protecting group employed is usually not critical.Suitable protecting groups for various situations are well known tothose skilled in the art. A large number of protecting groups andcorresponding chemical cleavage reactions are described in ProtectiveGroups in Organic Synthesis, Theodora W. Greene (John Wiley & Sons,Inc., New York, 1991, ISBN 0-471-62301-6); and Kocienski, Philip J.,Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994); andthe references cited therein. Removable protecting groups includeconventional groups such as allyl, benzyl, acetyl, chloroacetyl,thiobenzyl, benzylidine, phenacyl, methyl methoxy, silyl ethers (e.g.,trimethylsilyl (TMS), t-butyl-diphenylsilyl (TBDPS), ort-butyldimethylsilyl (TBS)), esters including sulfonic acid esters,carbonates, sulfates, and sulfonates, carbamates, and the like, or anyother group that can be introduced chemically onto a functionality andlater selectively removed either by chemical or enzymatic methods inmild conditions compatible with the nature of the product.

The term “substituted” indicates that one or more hydrogen atoms on thegroup indicated in the expression using “substituted” is replaced with a“substituent”. The number referred to by ‘one or more’ can be apparentfrom the moiety one which the substituents reside. For example, one ormore can refer to, e.g., 1, 2, 3, 4, 5, or 6; in some embodiments 1, 2,or 3; and in other embodiments 1 or 2. The substituent can be one of aselection of indicated groups, or it can be a suitable group known tothose of skill in the art, provided that the substituted atom's normalvalency is not exceeded, and that the substitution results in a stablecompound. Suitable substituent groups can be included on substratesdescribed herein, such as the various heavy atom chains and ringstructures, include, e.g., alkyl, alkenyl, alkynyl, alkoxy, halo,haloalkyl, hydroxy, hydroxyalkyl, aryl, aroyl, (aryl)alkyl (e.g., benzylor phenylethyl), heteroaryl, heterocycle, cycloalkyl, alkanoyl,alkoxycarbonyl, amino, alkylamino, dialkylamino, trifluoromethyl,trifluoromethoxy, trifluoromethylthio, difluoromethyl, acylamino, nitro,carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl,alkylsulfonyl, arylsulfinyl, arylsulfonyl, heteroarylsulfinyl,heteroarylsulfonyl, heterocyclesulfinyl, heterocyclesulfonyl, phosphate,sulfate, hydroxyl amine, hydroxyl (alkyl)amine, and cyano. Additionally,suitable substituent groups can be, e.g., —X, —R, —B(OH)₂, —B(OR)₂, —O⁻,—OR, —SR, —S⁻, —NR₂, —NR₃, ═NR, —CX₃, —CN, —OCN, —SCN, —N═C═O, —NCS,—NO, —NO₂, ═N₂, —N₃, —NC(═O)R, —C(═O)R, —C(═O)NRR, —S(═O)₂O⁻, —S(═O)₂OH,—S(═O)₂R, —OS(═O)₂OR, —S(═O)₂NR, —S(═O)R, —OP(═O)O₂RR, —P(═O)O₂RR,—P(═O)(O⁻)₂, —P(═O)(OH)₂, —C(═O)R, —C(═O)X, —C(S)R, —C(O)OR, —C(O)O⁻,—C(S)OR, —C(O)SR, —C(S)SR, —C(O)NRR, —C(S)NRR, or —C(NR)NRR, where eachX is independently a halogen (“halo”): F, Cl, Br, or I; and each R isindependently H, alkyl, aryl, (aryl)alkyl (e.g., benzyl), heteroaryl,(heteroaryl)alkyl, heterocycle, heterocycle(alkyl), or a protectinggroup. As would be readily understood by one skilled in the art, when asubstituent is keto (═O) or thioxo (═S), or the like, then two hydrogenatoms on the substituted atom are replaced. In some embodiments, one ormore of the substituents above are excluded from the group of potentialvalues for substituents on the substituted group, or on a compounddefined by a formula describing a group of compounds. Additionally, ionsor radicals of the substituents recited above can be nucleophiles orelectrophiles that can be used in a reaction described herein, toprovide various reaction products.

Substituted alkyl groups include, for example, haloalkyl groups. Theterm “haloalkyl” refers to alkyl as defined herein substituted by 1-4halo groups, which may be the same or different. Representativehaloalkyl groups include, by way of example, trifluoromethyl,3-fluorododecyl, 12,12,12-trifluorododecyl, 2-bromooctyl,3-bromo-6-chloroheptyl, perfluorooctyl, and the like.

As to any of the above groups, which contain one or more substituents,it is understood, of course, that such groups do not contain anysubstitution or substitution patterns that are sterically impracticaland/or are synthetically non-feasible. The substrates described hereinmay contain asymmetrically substituted carbon atoms, and may be isolatedin optically active or racemic forms. All chiral, diastereomeric,racemic forms and all geometric isomeric forms of a structure are partof this invention.

The term “contacting” refers to the act of touching, making contact, orof bringing to immediate or close proximity, including at the cellularor molecular level, for example, to bring about a physiologicalreaction, a chemical reaction, or a physical change, e.g., in a solutionor in a reaction mixture.

An “effective amount” refers to an amount effective to bring about arecited effect. For example, an amount effective can be an amounteffective to initiate a reaction and to provide a discernable amount ofproducts. Determination of an effective amount is well within thecapacity of persons skilled in the art. The term “effective amount” isintended to include an amount of a compound described herein, or anamount of a combination of compounds described herein, e.g., that iseffective to initiate a reaction described herein. For example, thereactions described herein can include an effective amount of catalyst,i.e., an amount necessary to facilitate a reaction. Likewise, thereactions can include an effective amount of a solvent, i.e., an amountof solvent necessary to dissolve the reactants and reagents to asufficient extent to facilitate a reaction. Thus, an “effective amount”generally means an amount that provides the desired outcome.

An “allene” group refers to three contiguous carbon atoms linkedtogether by two carbon-carbon double bonds. An allene can bemono-substituted, di-substituted, tri-substituted, or tetrasubstituted.A proximal allene carbon refers to the carbon of the allene group thatis closest to another reference group, with respect to the shortestnumber of atoms in a chain linking the reference group to the allenecarbon.

A “nucleophile-addition product” refers to the product of a reaction inwhich a nucleophile has been added to a substrate.

An “electrophile-addition product” refers to the product of a reactionin which an electrophile has been added to a substrate.

A “one-pot reaction” refers to a reaction that is carried out in onereaction vessel without working up the reactants and products in betweensteps of the overall reaction. Such steps can include aziridinations,oxidations, reductions, hydrolyses, and combinations thereof.

The term “enantiomerically enriched” refers to mixtures that have oneenantiomer present to a greater extent than another. The term“enantiomerically enriched” can refer to a mixture having at least about50% enantiomeric excess (“ee”). The term can also refer to a mixturehaving at least about 75% ee; at least about 80% ee; at least about 85%ee; i at least about 90% ee; at least about 92% ee; at least about 95%ee; at least about 98% ee; or at least about 99% ee. As would be readilyrecognized by one of skill in the art, the compounds described hereincan be prepared in enantiomerically enriched form. Likewise, thecompounds described herein can be prepared in diastereomericallyenriched form, and thus can have a diastereomeric excess in percentagessimilar to those recited above for an enantiomeric excess, wherein thediastereomeric excess is typically defined as a diastereomeric ratio(“dr”).

The following Examples are intended to illustrate the above inventionand should not be construed as to narrow its scope. One skilled in theart will readily recognize that the Examples suggest many other ways inwhich the invention could be practiced. It should be understood thatnumerous variations and modifications may be made while remaining withinthe scope of the invention.

EXAMPLES Example 1 Allene Functionalization Via Bicyclic MethyleneAziridines

This example describes the use of bicyclic methylene aziridines (MAs) asscaffolds for the functionalization of each of the three carbons of anallene (Scheme 1-A). The reactions described herein thus allow for thetransformation of allenes into synthetic motifs containing threecontiguous carbon-heteroatom bonds. The bicyclic methylene aziridines(MAs) can be prepared via intramolecular allene aziridination, asdescribed herein.

Olefins are popular substrates for a host of oxidative transformationsdesigned to introduce new C—N bonds into molecules. However,considerably less effort has been devoted to oxidations of allenes,despite the potential to efficiently generate three new contiguousheteroatom-bearing chiral centers. This example describes the use ofintramolecular allene amination as a key step for the stereoselectiveand flexible functionalization of allenes (Atkinson and Malpass,Tetrahedron Lett. 1975, 4305; Bingham and Gilbert, J. Org. Chem. 1975,40, 224).

One approach toward this goal is illustrated below in Scheme 1-1.Reaction of an intermediate bicyclic methylene aziridine (MA) 2 with anucleophile would generate enecarbamate 3. Sequential addition of anelectrophile and a hydride source to reduce the resultant imine couldflexibly generate motifs such as 4 (Robertson et al., Org. Biomol. Chem.2010, 8, 3060; Shipman, Synlett. 2006, 3205).

where R is, for example, R¹ as defined herein for Formula I.

Despite the great potential of bicyclic MAs to serve as scaffolds forallene oxidation, a significantly more detailed understanding of theirpreparation and reactivity is needed to provide new synthetic methodsand improved synthetic routes to important compounds. A recent report onallene aziridination utilizing N-tosyloxycarbamates as nitreneprecursors reported low yields of MAs and limited substrate scope(Robertson et al., Org. Biomol. Chem. 2010, 8, 3060). Thus, a firstchallenge was to examine factors including substrate, nitrene precursor,catalyst, and oxidant identity, to improve the efficiency of alleneaziridination to synthetically useful levels and reasonablestereoselectivities.

Attempts to utilize N-tosyloxycarbamates as nitrene precursors were metwith limited success for the synthesis of 7 (Table 1-1, entries 1-4),similar to previously reported results (Robertson et al., Org. Biomol.Chem. 2010, 8, 3060). The competitive formation of C—H amination product8 was a recurring issue, as well as unproductive tosylation of 5 withanother molecule of itself to yield 9 (Hayes et al., Chem. Commun. 2006,4501). The use of sulfamate 6 was successful and gave no competing C—Hamination, but ring-opening of the labile MA to 10 (entry 5) wasproblematic. Increasing the tether length between the allene and thesulfamate to three carbons (11, entry 6) completely suppressedring-opening of the desired 11a, but also gave significant amounts ofthe C—H amination product 11b.

TABLE 1-1 N-Tosyloxycarbamate and sulfamate precursors.

entry substrate products

1^(a) 2 mol % Rh₂(OAc)₄ 11% 7, 19% 8, 40% 9 2^(a) 2 mol % Rh₂(NHTFA)₄16% 7, 29% 8, 20% 9 3^(a) 2 mol % Rh₂(esp)₂ 21% 7, 15% 8, 22% 9 4^(a,b)2 mol % Rh₂(esp)₂ 42% 7, 15% 8. 41% 9 5^(c)

90%^(d) 6^(e)

38%

42% ^(a)K₂CO₃, 0.1M in acetone. ^(b)Substrate was added over 2 h and theacetone was dried over 4 A MS. ^(c)2.0 equiv PhIO, 4 A MS, CH₂Cl₂, rt.^(d)Products of hydrolysis of 10 were also observed. ^(e)2.0 equivPhI(OAc)₂, MgO, CH₂Cl₂, 40° C.

For the purposes of isolating the target MAs, it was found thatcarbamates provided the best balance between the reactivity of thenitrene precursor and the subsequent stability and reactivity of theproduct. A series of allenic carbamates were subjected to variousreaction conditions as illustrated in Table 1-2. It was found that theRh₂(OAc)₄ and Rh₂(oct)₄ (oct=O₂CC₇H₁₅) catalysts previously used in thistype of chemistry did not perform well in our hands. Rh₂esp₂(esp=α,α,α′,α′-tetramethyl-1,3-benzenedipropionate) and Rh₂(TPA)₄(TPA=triphenylacetate) proved to be more effective catalysts, givingcomplete conversion of the carbamate in most cases.

TABLE 1-2 Carbamate precursors for allene aziridination.

entry conditions products 1 B: 67%^(a) (39%) 12a E:Z >9:1 29%^(a) (17%)12b Z:E >9:1

2 B: 87% 13a E:Z 2.4:1

3   A: B: C: D: 14a 46% E:Z 1.5:1 42% E:Z 4.1:1 66% E:Z 3:1 80% E:Z 4:114b 44% 45% 16% 15%

4 D: 46%^(b) 15a E only 21% 15b

5 C: 49% 16a E:Z 1:1 17% 16b

6 D: 45%^(b) 17a E only 23% 17b

7 D: 48% 18a (E:Z 1.5:1) 31% 18b (dr 2:1)

8 B: 10% 19a E:Z 2.8:1 72% 19b D: 5% 19a E:Z 1.9:1 84% 19b

9 B: 21% 20a E:Z 3:1 57% 20b D: 44% 20a E:Z 2.6:1 48% 20b

10 B: 94% 21a E:Z 3:1

A: Rh₂(esp)₂, 2.0 equiv PhI(OAc)₂, 2.6 equiv MgO, CH₂Cl₂, 35° C. B:Rh₂(esp)₂, 2.0 equiv PhI(OPiv)₂, 2.6 equiv MgO, CH₂Cl₂, 35° C. C:Rh₂(esp)₂, 2.0 equiv PhIO, 4 A MS, CH₂Cl₂, rt D: Rh₂(TPA)₄, 2.0 equivPhIO, 4 A MS, CH₂Cl₂, rt ^(a)Based on recovered starting material.^(b)None of the Z was isolated.

The choice of oxidant was also highly significant, as the leaving groupreleased from the PhI(OAc)₂ or PhI(OPiv)₂ oxidants can ring-opensensitive MAs to yield the corresponding enecarbamates. For example(Table 1-2, entry 1), the Z isomer of MA 12a was susceptible toring-opening by pivalate to give 12b in addition to the desired 12a.Placing a methyl group at the carbon α to the allene (entry 2)suppressed ring-opening to give an 87% yield of MA 13a as a 2.4:1mixture of E:Z isomers at the olefin, with the methyl group and theaziridine proton maintaining a trans relationship in both alkenestereoisomers as observed by ¹H NMR. The use of PhIO in the presence of4 Å molecular sieves minimized the MA ring-opening and was the oxidantof choice for most of the reactions in Table 1-2.

Competing C—H amination can occur when the tether between the allene andthe carbamate is two or more carbons. As illustrated in entry 3, thenature of the catalyst and oxidant influenced the aziridination vs. C—Hamination ratio and the overall yield of the reaction. A Rh₂(esp)₂catalyst with PhI(OAc)₂ (Condition A) gave good conversion to a mixtureof 14a and 14b, but with little or no selectivity for aziridination overC—H amination. Changing the oxidant to PhI(OPiv)₂ (Condition B) improvedthe E:Z ratio of the MA product from 1.5:1 to 4.1:1, but did notincrease the ratio of 14a:14b. Switching the oxidant to PhIO (ConditionC) increased the ratio of 14a:14b to 4:1, with a 66% yield of the MA.Finally, changing the catalyst to Rh₂(TPA)₄ resulted in a 5.3:1 ratio of14a:14b, with an 80% yield of the desired MA 14a (condition D).

Changing the side chain on the allene in combination with the use ofRh₂(TPA)₄ as the catalyst gave only the isolated E isomer (entries 4 and6), but C—H amination was competitive. Placement of alkyl groups atpositions α or β to the allene resulted in increased amounts of C—Hamination products (entries 7-9), although the use of Rh₂(TPA)₄ didimprove the aziridination/C—H amination ratio to some extent. Finally,shutting down the possibility of C—H amination (entry 10) gave anexcellent 94% yield of the desired MA 21a.

NOESY 1D studies indicate that the E olefin geometry is present in themajor product (see the General Experimental Information below forfurther details). Indirect evidence that interactions between thenitrenoid intermediate and the alkyl chain play a role in determiningthe E:Z ratio is suggested by entry 3 in Table 1-2. The more stericallydemanding Rh₂(TPA)₄ complex increased the E:Z ratio from 1.5:1 to around4:1. Increasing the bulk of the Rh ligands can improve thestereoselectivity of the aziridination.

The reactions in Table 1-2 represent the first reliable methods toaccess bicyclic MAs bearing electron-withdrawing groups on the aziridinenitrogen. Next, nucleophiles were evaluated for the preparation of anenecarbamate (Scheme 1-1, 3) intermediate via aziridine ring-opening.The additional ring strain present in 14a could allow for milderconditions than would typically be expected for aziridine ring opening(Scheme 1-2). Indeed, carboxylic acid nucleophiles gave theenecarbamates 22 and 26 in excellent yields, while the use of TMSCl atroom temperature (˜23° C.) gave 24 in good yield.

Because MA ring-opening using carboxylic acids as nucleophiles isrelatively facile, Lewis acids could also likely activate the aziridinetoward ring-opening with neutral nucleophiles. Indeed, the use ofSc(OTf)₃ as a mild Lewis acid in the presence of methanol and thiophenolpromoted the ring-opening of 14a to give 27 and 28 in modest yields. Noreaction occurred in the absence of the Lewis acid. Reaction with acyanide nucleophile was also improved in the presence of a Lewis acid,although the double bond migrated to give an isomeric enecarbamate 25.Finally, treatment of 14a with NaN₃/TMSCl generated 23 in 82% yield,likely via initial ring-opening of the MA, followed by a[3,3]-sigmatropic rearrangement (Feldman et al., J. Am. Chem. Soc. 2005,127, 13444; VanderWerf and Heasley, J. Org. Chem. 1966, 31, 3534.). Asshown by the results in Scheme 1-2, carboxylic acids were found to behighly effective nucleophiles.

As illustrated in entry 1 of Table 1-3, eliminating the ring-openingstep and simply treating the MA 14a with NBS in a mixture of THF/H₂Ogave 29 with an initial dr of 5.5:1. The α-bromoketone epimerized slowlyover time to give a 1.1:1 mixture of diastereomers. Loss ofstereochemical integrity was also noted when 26 was subjected to similarconditions, giving the tetrasubstituted bromoalkene 30 as a 2.3:1mixture of E:Z isomers (entry 2).

TABLE 1-3 Formation of three contiguous carbon-heteroatom bonds fromallenes. entry substrate conditions product 1

  14a 1.1 equiv NBS THF/H₂O, rt 63% dr 5.5:1^(a)

  29 2

  26 1.4 equiv NBS THF/H₂O, rt 68% E:Z 2.3:1

  30 3 26 1.1 equiv NBS THF/H₂O, rt NaCNBH₃/AcOH 73% dr 10:1

  31 4

  13 Condition B (Table 2) then PhtNNH₂, PhI(OAc)₂, K₂CO₃ 46% dra:b >95:5 dr ab:c 2.4:1

  32 ^(a)Compound epimerized to a 1.1:1 mixture upon standing.

Isomerization of an intermediate imine could lead to the brominatedolefin. This prompted the addition of NaCNBH₃ as a reductant to thereaction mixture, whereupon 31 was obtained in 73% yield with a dr of10:1 (see the General Experimental Information below for details and aproposed stereochemical model). Anchimeric assistance from the acetategroup of the enecarbamate may play a role in controlling thestereochemical outcome of the reaction. This result, coupled with theease of ring-opening MAs with acids, provides an important step towardflexible, stereoselective methods for allene functionalization.

The power of allene aziridination to generate multiple carbon-heteroatombonds in a single pot was further demonstrated by a tandemaziridination/ring-opening of the allene 13 to 32 (Table 1-3, entry 4).The substrate was treated under Condition B (Table 1-2) to form theintermediate MA. N-aminophthalimide and additional oxidant were thenadded to the same pot to yield the unusual spiroaminal 32 in 46% yield,where four new carbon-heteroatom bonds have been formed in a single pot.The stereochemistry between the Me and OAc groups at a and b wasexclusively trans by ¹H NMR (see the General Experimental Informationbelow for further details). The 2.4:1 E:Z ratio of the MA olefin isomers(see 13a, Table 1-2, entry 2) appears to have been translated from theintermediate MA into a 2.4:1 dr in the final product 32. This resultindicates that better control of the E:Z stereochemistry in the MAformation translates into excellent dr in the spiroaminal products.Additional discussion of spiroaminal products can be found in Example 2below.

Thus, a synthetically useful approach for the preparation of bicyclicMAs activated by electron-withdrawing groups has been described. Thepotential of these MAs as scaffolds for the construction of motifsbearing three contiguous heteroatom-bearing carbons has beendemonstrated. Use of enantioenriched allenes (Ogasawara, Tetrahedron:Asymmetry 2009, 20, 259; Kim and Williams, Curr. Opin. Drug Disc. 2006,11, 870) for the asymmetric syntheses of MAs can provide thecorresponding enantioenriched products. A variety of nucleophiles andelectrophiles for efficient and flexible multi-component reactions thatinstall multiple carbon-heteroatom bonds into a simple allene precursorhas also been demonstrated.

I. General Experimental Information.

All glassware was either oven-dried overnight at 130° C. or flame-driedunder a stream of dry nitrogen prior to use. Unless otherwise specified,reagents were used as obtained from the vendor without furtherpurification. Tetrahydrofuran and diethyl ether were freshly distilledfrom purple Na/benzophenone ketyl. Dichloromethane, acetonitrile andtoluene were dried over CaH₂ and freshly distilled prior to use. Allother solvents were purified in accordance with “Purification ofLaboratory Chemicals” (Armarego and Chai, 6^(th) ed., Elsevier:Burlington, Mass., 2009). Air- and moisture-sensitive reactions wereperformed either in a Braun LabStar glovebox under an atmosphere ofnitrogen or using standard Schlenk techniques under an atmosphere ofnitrogen. Analytical thin layer chromatography (TLC) was performedutilizing pre-coated silica gel 60 F₂₅₄ plates containing a fluorescentindicator, while preparative chromatography was performed usingSilicaFlash P60 silica gel (230-400 mesh) via Still's method (Still,Kahn, and Mitra, J. Org. Chem. 1978, 43, 2923). Unless otherwise stated,the mobile phases for column chromatography were mixtures ofhexanes/ethyl acetate. Columns were typically run using a gradientmethod, beginning with 100% hexanes and gradually increasing thepolarity using ethyl acetate. Various stains were used to visualizereaction products, including p-anisaldehyde, KMnO₄, ceric ammoniumnitrate and phosphomolybdic acid in ethanol stain.

¹H NMR and ¹³C NMR spectra were obtained using Bruker-300, VarianInova-500, Varian Unity-500 or Varian Inova-600 NMR spectrometers. For¹H NMR, chemical shifts are reported relative to residual protiatedsolvent peaks (δ 7.26, 2.49, 7.15 and 4.80 ppm for CDCl₃, (CD₃)₂SO, C₆D₆and CD₃OD respectively). ¹³C NMR spectra were measured at either 125 MHzor 150 MHz on the same instruments noted above for recording ¹H NMRspectra. Chemical shifts were again reported in accordance to residualprotiated solvent peaks (δ 77.0, 39.5, 128.0 and 49.0 ppm for CDCl₃,(CD₃)₂SO, C₆D₆, and CD₃OD, respectively). IR spectral data were obtainedusing a Bruker Vector 22 spectrometer using either a thin film or an ATRadapter. Melting points were obtained with a MeI-Temp II (LaboratoryDevices, Inc.) melting point apparatus. Accurate mass measurements wereacquired at the University of Wisconsin, Madison using a Micromass LCT(electrospray ionization, time-of-flight analyzer or electron impactmethods).

II. Preparation of Allene Substrates.

The preparations of the majority of the allene substrates wereaccomplished according to literature procedures (Lang and Hansen, Helv.Chim. Acta 1980, 63, 438; Alexakis et al., Tetrahedron Lett. 1985, 26,4197; Buchner et al., Org. Lett. 2009, 11, 2173; Lang and Hansen, Org.Synth. Coll. Vol. 7, 1990, 232; Henderson and Heathcock, J. Org. Chem.1988, 53, 4736).

Compound S1.

An oven-dried 250 mL flask was charged with LiAlH₄ (2.7 g, 71.4 mmol,4.0 equiv) and 50 mL of THF. The suspension was cooled to 0° C. and asolution of the ester (3.5 g, 17.8 mmol, 1.0 equiv) in 25 mL of THF wasadded dropwise over 40 min. The reaction mixture was warmed slowly to rtand stirred for 4 h, or until complete conversion was seen by TLC (3:1hexanes/ethyl acetate). The reaction was cooled back to 0° C. andquenched carefully by successive additions of 2.7 mL of water, 2.7 mL of15% NaOH and 8.1 mL of water. The mixture was stirred vigorously at rtfor 30 min, the salts removed by filtration and the filtrate dried overMgSO₄. The volatiles were removed under reduced pressure to give theproduct as a colorless oil in 92% yield. The material was sufficientlypure by ¹H NMR and was used without further purification. ¹H NMR (300MHz, CDCl₃) δ 5.13 (m, 2H), 3.71 (q, 2H, J=6.0 Hz), 2.26 (ddd, J=6.3,6.3, 2.9 Hz, 2H), 1.99 (ddd, J=7.0, 7.0, 2.9 Hz, 2H), 1.6-1.2 (m, 8H),0.90, (t, J=6.3 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 204.8, 91.8, 87.3,62.2, 32.5, 31.5, 29.0, 22.7, 14.2.

Compound S2.

To a dry 100 mL Schlenk flask was added N,N-diisopropylamine (2.9 mL,20.9 mmol) and 40 mL of dry THF. The solution was cooled to −78° C.under an atmosphere of nitrogen, then n-BuLi (8.77 mL, 19.0 mmol, 2.17 Min hexanes) was added dropwise over 20 min. The resulting solution wasstirred for an additional 20 min at −78° C., warmed to 0° C. in an icebath and stirred for 10 min to ensure complete LDA formation. Thesolution was once again cooled to −78° C. and the allenic ester (4.0 g,19.0 mmol) dissolved in 10 mL dry THF was added dropwise to the cold LDAsolution. MeI (1.2 mL, 19.0 mmol) was then added dropwise to the redsolution. The reaction mixture was stirred for 1 h at −78° C., then anadditional 30 min at 0° C. The mixture was quenched with 20 mL ofsaturated NH₄Cl and extracted with three portions of EtOAc. The combinedorganics were washed three times with brine, dried over Na₂SO₄ andfiltered. The filtrate was concentrated under reduced pressure to yieldthe methylated product as a yellow oil (3.8 g, 89%), which was usedwithout further purification. ¹H NMR (300 MHz, CDCl₃) δ 5.31 (m, 1H),5.24 (dd, 1H, J=6.8, 6.1 Hz), 4.10 (q, 2H, J=7.4 Hz), 1.98 (m, 2H),1.4-1.16 (overlapping signals, 15H total), 0.86 (t, 3H, J=6.0 Hz). ¹³CNMR (75 MHz, CDCl₃) δ 202.1, 176.5, 97.7, 94.4, 60.6, 42.3, 31.4, 28.7,25.5, 25.3, 22.5, 14.1, 14.0.

III. Preparation of Allenic N-Tosyloxycarbamates, Sulfamates andCarbamates.

General Procedure for the Preparation of N-Tosyloxycarbamates.

The N-tosyloxycarbamate for the studies described in Table 1-1 wasprepared according to a general literature procedure described by Lebeland co-workers (Org. Lett. 2007, 9, 4797). General procedure for thepreparation of sulfamates. The following sulfamates were preparedaccording to a general literature procedure described by Du Bois andco-workers (J. Am. Chem. Soc. 2001, 123, 6935).

Compound 6.

The product was obtained as a colorless oil in 62% yield. ¹H NMR (300MHz, C₆D₆) δ 5.12 (m, 1H), 4.94 (m, 1H), 3.89 (overlapping signals, 4H),2.13 (br ddd, J=8.9, 6.9, 3.2 Hz, 2H), 1.93 (br ddd, J=10.1, 6.5, 3.2Hz, 2H), 1.30 (overlapping signals, 6H), 0.88 (br t, J=6.9 Hz, 3H). ¹³CNMR (75 MHz, C₆D₆) δ 204.9, 92.3, 86.1, 69.7, 31.5, 29.0, 28.8, 28.7,22.7, 14.1. HRMS (ESI) m/z calculated for [M+H]⁺ 234.1159, found234.1167.

Compound 11.

The product was obtained in 67% as a thick, colorless oil. ¹H NMR (500MHz, CDCl₃) δ 5.10 (m, 2H), 4.82 (br s, 2H), 4.25 (t, 2H, J=6.3 Hz),2.11 (m, 2H), 1.97 (m, 2H), 1.87 (m, 2H), 1.39 (m, 2H), 1.30 (m, 4H),0.89 (t, 3H, J=7.2 Hz). ¹³C NMR (125 MHz, CDCl₃) δ 204.0, 92.2, 89.2,70.8, 31.3, 28.8, 28.8, 28.0, 24.6, 22.5, 14.1. HRMS (ESI) m/zcalculated for [M+NH₄]⁺ 265.1581, found 265.1566.

General Procedure for the Preparation of Carbamates.

The following carbamates were prepared according to a general proceduredescribed by Du Bois and Espino (Angew. Chem. Int. Ed. 2001, 40, 598).

Compound 12.

The product was obtained in 99% yield as a thick oil that solidifiedupon storage in the freezer. ¹H NMR (300 MHz, CDCl₃) δ 5.22 (m, 2H),4.85 (br s, 2H), 4.58-4.42 (br m, 2H), 1.98 (m, 2H), 1.42-1.2 (severaloverlapping signals, 6H total), 0.86 (t, 3H, J=7.5 Hz). ¹³C NMR (75 MHz,CDCl₃) δ 205.2, 156.8, 92.9, 87.0, 63.5, 31.1, 28.6, 28.2, 22.3, 13.9.HRMS (ESI) m/z calculated for [M+Na]⁺ 206.1152, found 206.1155.

Compound 13.

The product was obtained in 96% yield as a thick oil that solidifiedupon storage in the freezer. ¹H NMR (300 MHz, CDCl₃) δ 5.27 (overlappingsignals, 3H), 5.06 (br s, 2H), 2.03 (br dd, 2H, J=13.5, 6.7 Hz),1.41-1.33 (overlapping signals, 9H total), 0.91 (br t, 3H, J=6.7 Hz).¹³C NMR (75 MHz, CDCl₃) δ 205.5, 157.4, 93.1, 87.3, 63.7, 31.4, 28.8,28.5 (2), 22.6, 14.2. HRMS (ESI) m/z calculated for [M+Na]⁺ 220.1308,found 220.1306.

Compound 14.

The product was obtained in 90% yield as a thick oil that solidifiedupon storage in the freezer. ¹H NMR (300 MHz, CDCl₃) δ 5.13-4.90(overlapping signals, 4H total), 4.02 (dd, 2H, J=6.9, 6.9 Hz), 2.21(ddd, 2H, J=10.1, 6.3, 3.2 Hz), 1.89 (ddd, 2H, J=7.0, 6.3, 3.2 Hz),1.31-1.20 (overlapping signals, 6H total), 0.80 (t, 3H, J=6.3 Hz). ¹³CNMR (75 MHz, CDCl₃) δ 204.8, 157.6, 92.0, 86.7, 64.6, 31.5, 28.9 (2),22.7, 14.2. HRMS (ESI) m/z calculated for [M+Na]⁺ 220.1308, found220.1300.

Compound 15.

The product was obtained in 78% yield as a thick, colorless oil thatsolidified upon storage in the freezer. ¹H NMR (500 MHz, CDCl₃) δ7.29-7.25 (Ar, 2H), 7.20-7.16, (Ar, 3H), 5.21-5.15 (m, 1H), 5.10-5.05(m, 1H), 4.74 (br s, 2H), 4.06 (t, J=7.5 Hz, 2H), 2.72 (dd, J=8.8, 8.8Hz, 2H), 2.34-2.23 (m, 4H). ¹³C NMR (125 MHz, CDCl₃) δ 204.7, 157.0,141.7, 128.5, 128.3, 125.8, 91.1, 87.2, 64.3, 35.3, 30.4, 28.6. HRMS(ESI) m/z calculated for [M−CNH₃O₂]⁺ 170.1091, found 170.184.

Compound 16.

The product was obtained in 89% yield as a thick, colorless oil thatsolidified upon storage in the freezer. ¹H NMR (500 MHz, CDCl₃) δ5.31-5.26 (m, 1H), 5.21-5.00 (overlapping signals, 3H total), 4.24 (ddd,J=6.4, 2.9, 1.5 Hz, 2H), 4.11 (t, J=6.7 Hz, 2H), 2.33 (qd, J=7.1, 3.0Hz, 2H), 1.14-1.02 (overlapping signals, 21H total). ¹³C NMR (125 MHz,CDCl₃) δ 203.9, 157.2, 92.5, 88.0, 64.1, 61.6, 28.3, 17.9, 11.9. HRMS(ESI) m/z calculated for [M−C₃H₇]⁺ 270.1520; found 270.1521.

Compound 17.

The product was obtained in 79% yield as a waxy solid. ¹H NMR (300 MHz,CDCl₃) δ 5.14 (m, 2H), 4.73 (br s, 2H), 4.12 (t, J=6.9 Hz, 2H), 2.32 (m,2H), 1.04 (s, 9H). ¹³C NMR (75 MHz, CDCl₃) δ 202.0, 157.1, 104.0, 88.6,64.7, 31.9, 30.3, 29.0. HRMS (ESI) m/z calculated for [M+.] 183.1254,found 183.1259.

Compound 18.

A Weinreb amide approach similar to Marcus et al., Angew. Chem. Int. Ed.2008, 47, 6379 was utilized to prepare the parent alcohol. The productwas obtained in 92% yield as a thick, colorless oil that solidified uponstorage in the freezer. ¹H NMR (300 MHz, CDCl₃) δ 5.06 (m, 2H), 4.84 (m,1H), 4.67 (br s, 2H), 2.24 (m, 2H), 1.98 (m, 2H), 1.31-1.42 (m, 6H),1.26 (d, J=6.3 Hz, 3H), 0.89 (t, J=6.3 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃)δ 205.1, 156.6, 91.1, 91.1, 86.1, 86.1, 71.3, 71.2, 35.9, 31.3, 28.8,28.7, 22.5, 19.6, 14.0. HRMS (ESI) m/z calculated for [M+Na]⁺ 234.1465,found 234. 1461.

Compound 19.

The compound was obtained in 76% yield as a thick oil that solidifiedupon storage in the freezer. ¹H NMR (300 MHz, CDCl₃) δ 5.05 (m, 2H),4.58 (br s, 2H), 2.45 (m, 2H), 1.98 (ddd, J=7.0, 7.6, 3.3 Hz, 2H), 1.38(overlapping signals, 12H), 0.89 (br t, J=6.8 Hz, 3H). ¹³C NMR (75 MHz,CDCl₃) δ 205.9, 156.4, 90.5, 86.0, 81.6, 41.2, 31.5, 29.1, 29.0, 26.1,26.1, 22.7, 14.3. HRMS (ESI) m/z calculated for [M+Na]⁺ 248.1621, found248.1620.

Compound 20.

The product was obtained in 96% yield as a thick oil that solidifiedupon storage in the freezer. ¹H NMR (300 MHz, CDCl₃) δ 5.13 (overlappingsignals, 4H), 3.94 (m, 2H), 2.47 (m, 1H), 1.99 (br dd, J=13.4, 6.7 Hz,2H), 1.34 (overlapping signals, 6H), 1.04 (br dd, J=6.8, 2.4 Hz, 3H),0.89 (br t, J=6.7 Hz, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 203.6, 157.7, 93.1,93.0, 69.6, 33.1, 31.5, 29.0 (2), 22.6, 16.9, 14.2. HRMS (ESI) m/zcalculated for [M+Na]⁺ 234.1463, found 234.1465.

Compound 21.

The product was obtained in 98% yield as a thick, colorless oil. ¹H NMR(300 MHz, CDCl₃) δ 5.20 (dd, 1H, J=6.5, 3.1 Hz), 5.06 (dd, 1H, J=3.1,2.9 Hz), 4.91 (br s, 2H), 3.86 (s, 2H), 1.98 (m, 2H), 1.42-1.24 (m, 6Htotal), 1.03 and 1.04 (2 s, 3H each), 0.89 (t, 3H, J=7.6 Hz). ¹³C NMR(75 MHz, CDCl₃) δ 202.5, 157.5, 98.5, 93.6, 73.4, 35.5, 31.6, 29.1,29.0, 25.1, 25.0, 22.7, 14.2. HRMS (ESI) m/z calculated for [M+Na]⁺248.1621, found 248.1620.

IV. Intramolecular Synthesis of Methylene Aziridines.

General Procedure A.

The allenic carbamate 14 (0.200 g, 1.02 mmol) and 11 mL of dry CH₂Cl₂were added to a dry 50 mL Schlenk flask. The solution was kept under anatmosphere of nitrogen and charged with MgO (0.106 g, 2.64 mmol) andRh₂(esp)₂ (0.0113 g, 0.0255 mmol). The resulting blue-green mixture wasstirred for 10 min at rt, then PhI(OAc)₂ (0.329 g, 1.02 mmol) was added,the flask fitted with a reflux condenser and the reaction mixture washeated to 35° C. in an oil bath for 1 h. Two additional 0.164 g (0.508mmol, 0.5 equiv) portions of PhI(OAc)₂ were added at 1 h intervals. Thereaction was monitored by TLC until complete (4 h). The heterogeneousmixture was concentrated under reduced pressure and the brick redresidue chromatographed on silica gel using a hexanes/EtOAc gradient.Pre-treatment of the silica gel column with 99.5:0.5hexanes/triethylamine, followed by flushing with four column volumes ofhexanes prior to loading the sample often improved the separation andprevented the decomposition of sensitive methylene aziridines.

General Procedure B.

A dry 50 mL Schlenk flask was charged with allenic carbamate 14 (0.200g, 1.02 mmol), followed by 6 mL of dry CH₂Cl₂. The solution was keptunder an atmosphere of nitrogen and charged with MgO (0.106 g, 2.64mmol) and Rh₂esp₂ (0.0192 g, 0.0250 mmol). The resulting blue-greenmixture was stirred for 10 min at rt, then 0.829 g PhI(OPiv)₂ (2.04mmol) dissolved in 5 mL of dry CH₂Cl₂ was added dropwise over the courseof 1.5 h via syringe pump. The flask was fitted with a reflux condenserand heated to 35° C. in an oil bath for 2 h or until TLC indicated thereaction was complete. The heterogeneous mixture was concentrated underreduced pressure and the brick red residue chromatographed on silica geleluting with a hexanes/EtOAc gradient.

General Procedure C.

A dry 50 mL Schlenk flask was charged with allenic carbamate 14 (0.370g, 1.88 mmol) and 19 mL of dry CH₂Cl₂. The solution was kept under anatmosphere of nitrogen and charged with 4 Å MS (0.925 g) and Rh₂esp₂(0.0356 g, 0.0470 mmol). The resulting blue-green mixture was stirredfor 10 min at rt, then PhIO (0.826 g, 3.75 mmol) was added in oneportion. The heterogeneous light green suspension was stirred at rtuntil complete by TLC (usually within 4 h). The resulting mixture wasconcentrated under reduced pressure, taken up in Et₂O and filteredthrough a pad of Celite. The filtrate was concentrated under reducedpressure and the brick red residue was chromatographed on SiO₂ geleluting using a hexanes/EtOAc gradient.

General Procedure D.

A dry 50 mL Schlenk flask was charged with the allenic carbamate 14(0.370 g, 1.88 mmol) and 19 mL of dry CH₂Cl₂. The solution was keptunder an atmosphere of nitrogen and charged with 4 Å MS (0.925 g) andRh₂(TPA)₄ (0.0660 g, 0.0470 mmol). The resulting blue-green mixture wasstirred for 10 min at rt, then PhIO (0.826 g, 3.75 mmol) was added inone portion, and the heterogeneous light green suspension was stirred atrt until complete by TLC (usually within 4 h). The resulting mixture wasconcentrated under reduced pressure, taken up in Et₂O and filteredthrough a pad of Celite. The filtrate was concentrated under reducedpressure and the brick red residue was chromatographed on silica geleluting with a hexanes/EtOAc gradient. See Hashioto et al., TetrahedronLett. 1992, 33, 2709.

Compound 9.

Obtained a mixture of diastereomers. ¹H NMR (300 MHz, CDCl₃) δ 7.92 and7.8 (2 d, 2H total, J=7.8 Hz), 7.41 and 7.32 (2 d, 2H total, J=8.0 Hz),5.2-5.03 and 4.9 (2 m, 2H total), 4.08 and 3.72 (2 dd, 2H total, J=6.8,6.8 Hz), 2.5 and 2.46 (2 s, 3H total), 2.31-1.84 (several m, 5H total),1.42-1.2 (br m, 6H total), 0.87 (2 overlapping t, 3H total). ¹³C NMR (75MHz, CDCl₃) δ 204.5, 204.4, 151.7, 146.5, 146.3, 132.9, 130.5, 129.7,129.0, 92.2, 91.5, 87.0, 85.3, 68.1, 61.9, 32.2, 31.2, 28.7, 28.6, 28.4,27.7, 22.3, 21.7, 21.6, 13.9.

Compound 10.

A pure sample of the product was obtained in 34% yield, with anadditional 58% yield isolated as approximately a 1:1 mixture of 10 andthe hydrolyzed ketone product following purification by columnchromatography (63% yield of 10 and 29% of the ketone). ¹H NMR (500 MHz,C₆D₆) δ 6.58 (s, 1H), 5.72 (t, J=6.5 Hz, 1H), 4.47 (t, J=13.0 Hz, 1H),4.22 (br s, 1H), 3.53 (br dt, J=13.0, 3.3 Hz, 1H), 1.69 (overlappingsignals, 3H), 1.55 (ddt, J=12.3, 3.3, 3.2 Hz, 1H), 1.18 (overlappingsignals, 6H), 0.87 (br t, J=6.8 Hz, 3H). ¹³C NMR (125 MHz, C₆D₆) δ131.6, 130.5, 64.1, 63.7, 36.1, 31.2, 28.7, 26.5, 22.4, 13.8. HRMS (ESI)m/z calculated for [M+Na]⁺ 272.0927, found 272.0925.

Compound 11a.

The product was obtained in 38% yield as a thick, colorless oil usingGeneral Procedure B. ¹H NMR (500 MHz, C₆D₆) δ 5.57 (t, J=6.8 Hz, 1H),3.70 (td, J=11.6, 1.7 Hz, 1H), 3.51 (dt, J=12.1, 3.5 Hz, 1H), 2.96 (s,1H), 1.92 (m, 1H), 1.82 (2 dd, J=7.3, 7.3 Hz, 2H total), 1.68 (m, 1H),1.04-1.36 (m, 7H), 0.88 (overlapping m and t, J=7.0 Hz, 4H). ¹³C NMR(125 MHz, C₆D₆) δ 128.2, 128.0, 127.8, 122.2, 106.8, 70.7, 45.9, 31.6,28.8, 28.6, 27.2, 26.6, 22.7, 14.1. HRMS (ESI) m/z calculated for[M+Na]⁺ 268.0978, found 268.0972.

Compound 11b.

The product was obtained using General Procedure B in 42% yield as athick, colorless oil that solidified to a white wax upon refrigeration.¹H NMR (500 MHz, C₆D₆) δ 5.12 (m, 1H), 4.80 (br s, 1H), 4.19 (dd,J=11.8, 11.8 Hz, 1H), 3.91 (m, 2H), 3.69 (m, 1H), 1.83 (m, 2H),1.07-1.33 (m, 7H), 0.89 (2 sets of triplets, J=7.0 Hz, 3H), 0.78 (m,1H). ¹³C NMR (125 MHz, C₆D₆) δ 203.2, 202.8, 96.2, 95.9, 91.4, 91.3,71.1, 71.0, 53.7, 31.6, 31.5, 29.6, 29.1, 29.0, 28.9, 28.7, 28.6, 22.7,14.2. HRMS (EI) m/z calculated for [M+H]⁺ 246.1159, found 246.1157.

Compound 12a.

The product was obtained in 39% yield as a single isomer having the Econfiguration about the olefin when PhI(OPiv)₂ was used as the oxidant(General Procedure B). If the remaining starting material was accountedfor, the yield increased to 67%. Another 17% yield of the product thathad been ring-opened by pivalic acid was obtained as a singlediastereomer 12b (29% based on recovered starting material). ¹H NMR (300MHz, CDCl₃) δ 5.74 (dd, 1H, J=6.9, 6.9 Hz), 4.45 (2 overlapping signals,2H), 3.68 (br m, 1H), 2.17 (2 d, 2H, J=7.0 Hz), 1.44-1.21 (severalsignals, 6H), 0.86 (t, 3H, J=7.0 Hz). ¹³C NMR (125 MHz, CDCl₃) δ 164.6,123.8, 107.6, 66.5, 41.4, 31.3, 28.7, 28.4, 22.5, 14.1. HRMS (ESI) m/zcalculated for [M+H]⁺ 181.1098, found 181.1090.

Compound 13a.

The product was obtained using General Procedure B as a 2.4:1 mixture ofE:Z isomers in 76% isolated yield using PhI(OPiv)₂ as the oxidant. A1.7:1 mixture of E:Z isomers was obtained when PhI(OAc)₂ was used as theoxidant. Major product: ¹H NMR (500 MHz, CDCl₃) δ 5.79 (dd, 1H, J=7.6,7.3 Hz), 4.86 (m, 1H), 3.64 (d, 1H, J=4.8 Hz), 2.16 (2 d, 2H, J=7.3 Hz),1.41-1.28 (overlapping signals, 9H), 0.86 (t, 3H, J=7.1 Hz). Minorproduct: ¹H NMR (500 MHz, CDCl₃) δ 5.53 (dd, 1H, J=7.4, 7.3 Hz), 4.86(m, 1H), 3.64 (d, 1H, J=4.8 Hz), 2.31 (2 d, 2H, J=7.7 Hz), 1.41-1.28(overlapping signals, 9H), 0.86 (t, 3H, J=7.1 Hz). Both isomers: ¹³C NMR(125 MHz, CDCl₃) δ 163.5 (2), 123.3, 123.2, 108.5, 108.4, 74.5, 74.4,45.7, 45.5, 31.2, 31.1, 29.6, 28.9, 28.8, 28.7, 27.6, 22.3, 18.2, 17.7,13.9 (2). HRMS (ESI) m/z calculated for [M+Na]⁺ 218.1152, found218.1162.

Compound 14a.

The product was obtained using General Procedure A in 46% yield aftercolumn chromatography as a thick, clear oil. The major isomer had the Econfiguration at the olefin. Both the yield and the E:Z ratio wereimproved by using the Rh₂(TPA)₄ catalyst and PhIO as the oxidant to givean 80% yield of 14a with a 4:1 E:Z ratio. ¹H NMR (300 MHz, CDCl₃) δ 5.55(dd, 1H, J=7.3, 6.8 Hz), 4.50 (dd, 1H, J=11.3, 2.1 Hz), 4.33 (ddd, 1H,J=11.0, 4.0, 2.6 Hz), 3.40 (dd, 1H, J=8.0, 6.5 Hz), 2.34 (m, 2H), 2.13(ddd, 2H, J=8.5, 7.2, 1.6 Hz), 1.59-1.2 (m, 6H), 0.85 (t, 3H, J=8.0 Hz).¹³C NMR (75 MHz, CDCl₃) δ 156.4, 125.5, 103.2, 68.8, 39.5, 31.3, 28.8,28.2, 24.3, 22.4 14.0. HRMS (ESI) m/z calculated for [M+H]⁺ 196.1333,found 196.1342.

Compound 14b.

The product was obtained using General Procedure A in 44% yield as aclear, thick oil. ¹H NMR (300 MHz, CDCl₃) δ 6.01 (br d, 1H, J=7.3 Hz),5.32 (m, 1H), 5.11 (m, 1H), 4.49 (dd, 1H, J=8.7, 8.2 Hz), 4.32 (dd, 1H,J=13.8, 6.1 Hz), 4.13 (dd, 1H, J=8.4, 5.9 Hz), 1.98 (m, 2H), 1.35-1.26(br m, 6H), 0.85 (t, 3H, J=6.7 Hz). ¹³C NMR (75 MHz, CDCl₃) δ 203.7,159.4, 95.4, 95.2, 91.1, 70.2, 52.1, 51.9, 31.1, 28.7, 28.5, 28.3, 28.2,22.3, 13.9. HRMS (ESI) m/z calculated for [M+H]⁺ 196.1333, found196.1339.

Compound 15a.

The product was obtained as a 1.3:1.0 mixture of E:Z isomers beforepurification via column chromatography using General Procedure D. Afterpurification, only the E isomer was present in 46% yield. ¹H NMR (500MHz, C₆D₆) δ 7.13-6.92 (Ar, 5H), 5.46 (dd, J=8.7, 7.7 Hz, 1H), 3.48(ddd, J=12.9, 10.9, 2.5 Hz, 1H), 3.32 (ddd, J=10.7, 4.2, 2.8 Hz, 1H),2.46-2.32 (m, 3H), 2.19-2.01 (m, 2H), 0.85 (ddt, J=14.7, 6.3, 2.8 Hz,1H), 0.38-0.30 (m, 1H). ¹³C NMR (125 MHz, C₆D₆) δ 154.9, 141.2, 128.6,128.3, 126.9, 125.9, 100.7, 67.9, 38.7, 35.3, 30.2, 22.9. HRMS (ESI) m/zcalculated for [M]⁺ 229.1098; found 229.1095.

Compound 15b.

The C—H amination product was present in 21% yield as an inseparablemixture of diastereomers. ¹H NMR (500 MHz, C₆D₆) δ 7.18-6.99 (Ar, 5H),6.34 (2 br s, NH, both diastereomers), 5.08-5.03 (m, 1H), 4.66-4.61 (m,1H), 3.62-3.58 (m, 1H), 3.44-3.40 (m, 2H), 2.60-2.43 (m, 2H), 2.14-2.03(m, 2H). ¹³C NMR: (125 MHz, C₆D₆) δ 203.6, 203.3, 159.5, 141.2, 128.5,128.4, 128.3, 126.0, 126.0, 125.9, 94.0, 93.9, 91.9, 69.4, 69.2, 51.4,51.2, 34.8, 29.8, 29.7. HRMS (ESI) m/z calculated for [M−CH₃NO₂]⁺168.0934, found 168.0929.

Compound 16a.

The product was obtained as a 1:1 mixture of E:Z isomers in 49% yield asa clear, yellow oil after column chromatography using General ProcedureC. E isomer: ¹H NMR (500 MHz, C₆D₆) δ 5.61 (dd, J=5.3, 4.7 Hz, 1H), 4.06(td, J=5.7, 0.8 Hz, 2H), 3.62 (ddd, J=12.1, 10.7, 2.4 Hz, 1H), 3.44(ddd, J=10.8, 3.9, 2.4 Hz, 1H), 2.78 (dd, J=8.6, 7.1 Hz, 1H), 1.20 (ddt,J=14.4, 6.3, 2.3 Hz, 1H), 1.02 (overlapping signals, 22H total). ¹³C NMR(125 MHz, C₆D₆) δ 154.6, 127.2, 101.8, 67.9, 60.6, 39.2, 23.7, 17.8,11.9. HRMS (ESI) m/z calculated for [M−C₃H₇]⁺ 268.1364; found 268.1355.Z isomer: ¹H NMR (500 MHz, C₆D₆) δ 5.49 (dd, J=7.8, 5.3 Hz, 1H), 5.09(dd, J=12.5, 8.2 Hz, 1H), 4.76 (dd, J=12.7, 4.9 Hz, 1H), 3.43 (ddd,J=12.8, 10.6, 2.0 Hz, 1H), 3.30 (ddd, J=10.8, 4.0, 2.3 Hz, 1H), 2.46(dd, J=9.3, 6.3 Hz, 1H), 1.03 (overlapping signals, 21H total), 0.87(ddt, J=14.6, 6.0, 2.8 Hz, 1H), 0.63 (m, 1H). ¹³C NMR (125 MHz, C₆D₆) δ154.1, 126.0, 102.9, 67.7, 59.9, 38.4, 23.2, 18.0, 12.0. HRMS (ESI) m/zcalculated for [M−C₃H₇]⁺ 268.1364; found 268.1363.

Compound 16b.

The C—H amination product was obtained in 17% yield as an inseparablemixture of diastereomers. ¹H NMR (500 MHz, C₆D₆) δ 5.72 (s br, 1H), 5.25(m, 1H), 4.72 (m, 1H), 4.10 (ddd, J=5.5, 2.9, 0.7 Hz, 1H), 4.04 (ddd,J=5.8, 2.9, 1.1 Hz, 1H), 3.74-3.63 (m, 1H), 3.55-3.51 (m, 2H), 1.07(overlapping signals, 21H total). ¹³C NMR (125 MHz, C₆D₆) δ 202.7,202.7, 159.1, 159.1, 95.8, 95.7, 93.2, 93.0, 69.3, 69.1, 60.9, 60.7,51.4, 51.2, 17.8, 11.9, 11.9. HRMS (ESI) m/z calculated for [M−C₃H₇]⁺268.1364; found 268.1370.

Compound 17a.

The product was obtained as a 2.2:1.0 mixture of E:Z isomers beforepurification via column chromatography using General Procedure D. Afterpurification, only the E isomer was present in 45% yield as a whitesolid (m.p. 84-87° C.). ¹H NMR (500 MHz, C₆D₆) δ 5.56 (br s, NH), 3.61(ddd, J=14.1, 11.7, 2.5 Hz, 1H), 3.45 (ddd, J=10.5, 4.0, 2.4 Hz, 1H),2.65 (dd, J=8.4, 6.3 Hz, 1H), 1.09 (ddt, J=14.5, 6.3, 2.1 Hz, 1H), 0.89(s, 9H), 0.83-0.76 (m, 1H). ¹³C NMR (125 MHz, C₆D₆) δ 155.1, 124.2,112.8, 67.8, 39.3, 32.2, 29.6, 24.1. HRMS (ESI) m/z calculated for [M]⁺181.1098, found 181.1106.

Compound 17b.

The CH-amination product was present in 23% yield as an inseparablemixture of diastereomers. ¹H NMR (500 MHz, C₆D₆) δ 6.90 (s br, NH), 6.82(s br, NH), 5.21 (dd, J=6.2, 1.7 Hz, 0.4H), 5.14 (dd, J=7.0, 2.0 Hz,0.5H), 4.83 (dd, J=5.5, 5.5 Hz, 0.5H), 4.76 (dd, J=6.2, 6.2 Hz, 0.4H),3.61 (overlapping signals, 3H total), 0.98 (overlapping signals, 9Htotal). ¹³C NMR (125 MHz, C₆D₆) δ 200.7, 200.6, 159.8, 159.8, 106.9,106.5, 93.5, 93.3, 69.5, 69.3, 51.5, 51.4, 31.7, 31.4, 29.7, 29.6. HRMS(ESI) m/z calculated for [M]⁺ 181.1098, found 181.1095.

Compound 18a.

The product was obtained as a 1.5:1 mixture of E:Z isomers in 48% yieldas a thick, colorless oil using General Procedure D. ¹H NMR (500 MHz,C₆D₆) δ 5.54 (t, J=6.9 Hz, 0.6H), 5.15 (t, J=7.6 Hz, 0.4H), 3.94 (m,1H), 2.51-2.77 (m, 2H), 1.94 (app q, J=7.3 Hz, 2H), 1.08-1.36 (m, 7H),0.86 (t, J=7.1 Hz, 3H), 0.81 (2 doublets, J=6.3, 5.9 Hz, 3H total). ¹³CNMR (125 MHz, C₆D₆) δ 155.5, 155.1, 126.9, 126.5, 102.2, 101.3, 76.2,75.9, 38.5, 38.4, 31.4, 31.3, 30.7, 30.7, 29.7, 28.8, 28.1, 27.2, 22.5,22.5, 20.2, 20.1, 13.9, 13.9. HRMS (EI) m/z calculated for [M+H]⁺210.1489, found 210.1482.

Compound 18b.

The product was obtained as an inseparable mixture of stereoisomers(˜2:1 approximate dr for C—H amination) in 31% as a thick, colorless oilusing General Procedure D. ¹H NMR (500 MHz, C₆D₆) δ 7.22 (br s, 1H),5.16 (m, 1H), 4.84 (m, 0.6H), 4.74 (m, 0.4H), 4.16 (m, 0.4H), 3.99 (m,0.6H), 3.67 (m, 0.4H), 3.42 (m, 0.6H), 1.87 (m, 2H), 1.17-1.40 (m, 6H),0.80-0.98 (overlapping doublets and triplets, 6H). ¹³C NMR (125 MHz,C₆D₆) δ 204.2, 203.9, 203.9, 159.7, 159.3, 94.7, 94.5, 94.3, 94.2, 91.1,91.0, 88.5, 78.5, 75.6, 75.5, 59.2, 59.0, 55.7, 55.3, 31.3, 31.2, 28.6,28.5, 28.4, 28.3, 22.5, 22.5, 18.8, 18.6, 15.6, 15.5, 13.9, 13.9. HRMS(EI) m/z calculated for [M+Na]⁺ 232.1308, found 232.1305.

Compound 19a.

The product was obtained as an oil in 10% (Condition B) yield as a 2.8:1mixture of E:Z isomers. Condition D gave a 5% yield of the product as a1.9:1 mixture of E:Z isomers. ¹H NMR (500 MHz, C₆D₆) δ 5.57 (t, J=6.3Hz, 1H major), 5.17 (t, J=7.7 Hz, 1H minor), 2.67 (overlapping signals,2H total), 1.95 (br dd, J=14.0, 7.2 Hz, 2H), 1.17 (overlapping signals,16H total), 0.89 (overlapping signals, 9H). ¹³C NMR (125 MHz, C₆D₆) δ183.6, 155.3, 102.3, 101.4, 83.3, 36.9, 34.0, 31.3, 29.7, 28.7, 28.7,28.1, 27.2, 26.7, 24.3, 22.5, 22.5, 13.9, 13.9. HRMS (EI) m/z calculatedfor [M]⁺ 223.1567, found 223.1563.

Compound 19b.

The product was obtained as a colorless oil that solidified to a waxysolid upon refrigeration in 72% yield using General Procedure B and 84%yield using General Procedure D. ¹H NMR (500 MHz, C₆D₆) δ 7.02 (br s,1H), 5.12 (m, 1H), 4.74 (m, 1H), 3.50 (m, 1H), 1.84 (m, 2H), 1.22 (m,6H), 1.01 (four singlets, 6H), 0.84 (two triplets, J=7.2, 6.8 Hz, 3H).¹³C NMR (125 MHz, C₆D₆) δ 204.6, 204.4, 159.2, 94.7, 94.2, 89.4, 89.3,83.0, 82.9, 82.9, 61.9, 61.6, 31.6, 31.5, 28.9, 28.9, 28.7, 28.6, 27.1,22.9, 22.8, 14.2, 14.2. HRMS (ESI) m/z calculated for [M]⁺ 223.1567,found 223.1561.

Compound 20a.

The product was obtained as an oil in 21% yield as a separable 3:1mixture of E:Z diastereomers using General Procedure B. Majordiastereomer (E): ¹H NMR (500 MHz, C₆D₆) δ 5.55 (t, J=6.8 Hz, 1H), 3.48(t, J=10.8 Hz, 1H), 3.38 (dd, J=10.4, 3.8 Hz, 1H), 2.40 (d, J=8.1 Hz,1H), 1.90 (app q, J=7.1 Hz, 2H), 1.07-1.24 (m, 7H), 0.85 (t, J=7.2 Hz,3H), 0.37 (d, J=6.9 Hz, 3H). ¹³C NMR (125 MHz, C₆D₆) δ 155.4, 126.2,101.9, 73.7, 44.4, 31.6, 30.5, 28.9, 28.5, 22.8, 14.1, 13.1. HRMS (ESI)m/z calculated for [M]⁺ 209.1411, found 209.1402. Minor diastereomer(Z): ¹H NMR (500 MHz, C₆D₆) δ 5.55 (t, J=7.2 Hz, 1H), 3.76 (dd, J=10.6,2.5 Hz, 1H), 3.34 (dd, J=10.8, 3.0 Hz, 1H), 2.85 (d, J=6.6 Hz, 1H), 1.85(m, 2H), 1.44 (m, 1H), 1.16 (m, 1H), 0.85 (t, J=7.1 Hz, 3H), 0.48 (d,J=7.4 Hz, 3H). ¹³C NMR (125 MHz, C₆D₆) δ 155.2, 123.6, 103.7, 72.4,43.7, 31.6, 29.4, 28.8, 25.3, 22.7, 14.1, 12.6. HRMS (ESI) m/zcalculated for [M]⁺ 209.1411, found 209.1417.

Compound 20b.

The product was obtained as an oil in 48% yield. ¹H NMR (500 MHz, C₆D₆)δ 7.35 (br s, 1H), 7.28 (br s, 1H), 5.19 (m, 1H), 5.03 (m, 1H), 3.88 (m,1H), 3.55 (br d, J=8.8 Hz, 1H), 1.88 (m, 2H), 1.25 (overlapping signals,6H), 1.06 (br s, 3H), 0.90 (m, 3H). ¹³C NMR (125 MHz, C₆D₆) δ 201.8,159.4, 96.7, 96.6, 95.9, 95.7, 75.4, 56.6, 31.3, 28.6, 28.5, 25.3, 25.2,22.5, 13.9. HRMS (EI) m/z calculated for [M+H]⁺ 210.1489, found210.1495.

Compound 21a.

The desired product was obtained in 94% yield with less than 5% of thestarting material remaining. The product was a 3:1 mixture of E:Zisomers, where the major isomer has the bulky alkyl chain on the olefindirected towards from the gem dimethyl group of the ring, according toNOESY 1D experiments on both isomers. Major isomer: ¹H NMR (500 MHz,CDCl₃) δ 5.61 (t of d, 1H, J=7.3, 0.9 Hz), 4.23 (d, 1H, J=10.5 Hz), 3.81(d, 1H, J=9.8 Hz), 3.72 (s, 1H), 2.11 (dd, 2H, J=14.1, 7.1 Hz), 1.54 (m,2H), 1.42-1.29 (br m, 7H total), 0.87 (2 overlapping signals, 6H total).¹³C NMR (125 MHz, CDCl₃) δ 156.2, 123.2, 104.2, 77.8, 48.6, 31.3, 29.5,28.9, 28.6, 23.9, 22.4, 20.6, 13.9. HRMS (ESI) m/z calculated for [M+H]⁺224.1646, found, 224.1652. Minor isomer: ¹H NMR (500 MHz, CDCl₃) δ 5.32(dd, 1H, J=7.4, 5.3 Hz), 4.16 (d, 1H, J=10.3 Hz), 3.80 (d, 1H, J=10.7Hz), 3.08 (s, 1H), 2.39 (dd, 2H, J=14.6, 6.9 Hz), 1.42-1.21 (overlappingsignals, 9H total), 0.87 (2 overlapping signals, 6H total). ¹³C NMR (125MHz, CDCl₃) δ 155.5, 122.9, 105.2, 77.1, 48.8, 31.2, 29.4, 29.0, 27.3,23.9, 22.4, 20.6, 14.0. HRMS (ESI) m/z calculated for [M+Na]⁺ 246.1465,found 246.1467.

V. Ring-Opening of Methylene Aziridines.

Compound 22.

A solution of the E bicyclic methylene aziridine 14a (99.9 mg, 0.512mmol, 1.0 equiv) dissolved in 4 mL of CH₂Cl₂ was cooled to 0° C.Chloroacetic acid (159.9 mg, 1.7 mmol, 3.3 equiv) dissolved in 2 mL ofCH₂Cl₂ was slowly added to the reaction and the mixture allowed to warmto rt overnight. The mixture was concentrated under reduced pressure andpurified by removing the excess chloroacetic acid under high vacuum(˜0.1 mmHg) to give the product 22 in 99% yield. ¹H NMR (500 MHz, C₆D₆)δ 8.39 (NH), 5.76 (d, J=5.8 Hz, 1H), 5.07 (t, J=7.5 Hz, 1H), 3.72 (td,J=12.6, 3.9 Hz, 1H), 3.55-3.51 (m, 1H), 3.43 (d, J=2.3 Hz, 2H),1.93-1.69 (m, 3H), 1.23-1.09 (m, 7H), 0.87 (t, J=6.8 Hz, 3H). ¹³C NMR(125 MHz, C₆D₆) δ 165.7, 156.3, 130.46, 118.0, 68.4, 65.1, 40.3, 32.7,31.3, 29.3, 26.4, 22.5, 13.9. HRMS (ESI) m/z calculated for C₁₃H₂₀ClNO₄[M+H⁺] 1290.1154, found 290.1155.

Compound 23

(see also Bergmeier and Stanchina, J. Org. Chem. 1997, 62, 4449). Sodiumazide (40.1 mg, 0.62 mmol, 1.5 equiv) was dissolved in 1.5 mL of dry DMFand cooled to 0° C. Chlorotrimethylsilane (81 μL, 0.63 mmol, 1.5 equiv)was added to the solution over the course of 10 min and left to stir for30 min at 0° C. The reaction mixture was allowed to warm to rt andstirred for an additional 30 min and the E bicyclic methylene aziridine14a (81.9 mg, 0.42 mmol, 1.0 equiv) dissolved in 1.0 mL of DMF was addedwas added and the reaction mixture stirred overnight. After a totalreaction time of 18 h, the reaction mixture was passed through a plug ofsilica gel pretreated with 0.5% triethylamine, concentrated underreduced pressure, and purified via column chromatography (9:1hexanes/ethyl acetate-ethyl acetate) through silica gel pre-treated with0.5% triethylamine to afford 23 as a clear, colorless oil in 82% yield.¹H NMR (500 MHz, C₆D₆) δ 6.69 (NH), 4.33 (dd, J=4.1, 1.6 Hz, 1H), 3.64(t, J=5.7 Hz, 2H), 3.26 (t, J=7.2 Hz, 1H), 1.71-1.68 (m, 2H), 1.27-1.03(m, 8H), 0.84 (t, J=7.4 Hz, 3H). ¹³C NMR: (125 MHz, C₆D₆) δ 158.1,132.8, 106.5, 66.8, 66.6, 32.3, 31.2, 28.4, 25.7, 22.5, 13.8. HRMS (ESI)m/z calculated for C₁₁H₁₈N₄O₂ [M+H⁺] 261.1322, found 261.1317.

Compound 24

(see also Bergmeier and Stanchina, J. Org. Chem. 1997, 62, 4449). To asolution of freshly distilled chlorotrimethylsilane (50 μL, 0.04 mmol,1.5 equiv) in 1.5 mL THF cooled to −40° C. was added E bicyclicmethylene aziridine 14a (51.2 mg, 0.26 mmol, 1.0 equiv) in 1.5 mL ofTHF. The temperature was maintained for 2 h, then the reaction mixturewarmed to 0° C. for an additional 4 h until complete consumption of thestarting material was observed by TLC. The reaction mixture wasconcentrated under reduced pressure and purified via flash columnchromatography (9:1 hexanes/ethyl acetate-3:1 hexanes/ethyl acetate)through silica gel pre-treated with 0.5% triethylamine to obtain 24 as aclear colorless oil in 61% yield. ¹H NMR (500 MHz, C₆D₆) δ 7.74 (NH),4.88 (t, J=7.3 Hz, 1H), 4.69 (dd, J=5.0, 3.2 Hz, 1H), 3.88 (ddd, J=12.7,6.9, 2.9 Hz, 1H), 3.57 (ddd, J=12.7, 7.9, 3.1 Hz, 1H), 1.75-1.69 (ddt,J=15.5, 7.6, 2.8 Hz, 1H), 1.60-1.52 (m, 2H), 1.45-1.39 (m, 1H),1.18-1.13 (m, 2H), 1.07-1.02 (m, 4H), 0.85 (t, J=7.2 Hz, 3H). ¹³C NMR(125 MHz, C₆D₆) δ 156.6, 132.7, 121.1, 64.3, 52.8, 36.3, 31.1, 28.9,26.6, 22.4, 13.8. HRMS (ESI) m/z calculated for C₁₁H₁₈ClNO₂ [M+H⁺]232.1099, found 232.1110.

Compound 25

(see also Duran et al., J. Org. Chem. 2005, 70, 8616). A solution of theE bicyclic methylene aziridine 14a (61.3 mg, 0.31 mmol, 1.0 equiv)dissolved in 3 mL of DMF was cooled to 0° C. and treated with KCN (27.1mg, 0.42 mmol, 1.3 equiv) in one portion. The reaction mixture waswarmed to 10-20° C. for 2 h, then allowed to warm to rt. Additional KCN(70.0 mg, 1.1 mmol, 3.5 equiv) was added to the reaction mixture,followed by Sc(OTf)₃ (26.4 mg, 0.064 mmol, 0.2 equiv) in one portion.The reaction mixture was monitored by TLC and stirred overnight at rt.After a total reaction time of 26 h, the mixture was concentrated underreduced pressure and purified via flash column chromatography (9:1hexanes/ethyl acetate-1:1 hexanes/ethyl acetate) through silica gelpre-treated with 0.5% triethylamine to obtain 25 as a white solid(melting point: 100° C.-103° C.) in 60% yield. ¹H NMR (500 MHz, C₆D₆) δ7.50 (NH), 3.28 (dd, J=6.0, 4.7 Hz, 2H), 2.12 (t, J=7.6 Hz, 2H), 1.72(t, J=4.8 Hz, 2H), 1.36-1.16 (m, 8H), 0.88 (t, J=7.5 Hz, 3H). ¹³C NMR(125 MHz, C₆D₆) δ 155.6, 149.0, 118.8, 89.5, 65.6, 36.0, 31.3, 30.7,28.4, 28.0, 22.5, 13.9. HRMS (ESI) m/z calculated for C₁₂H₁₈N₂O₂ [M+H⁺]223.1442, found 223.1432.

Compound 26

(see also Bergmeier and Stanchina, J. Org. Chem. 1997, 62, 4449). Asolution of the E bicyclic methylene aziridine 14a (25.0 mg, 0.128 mmol,1.0 equiv) dissolved in 0.8 mL of dioxane was treated with glacialacetic acid (320 μL, 5.57 mmol, 44.0 equiv). The reaction mixture wasstirred at rt for 36 hours, concentrated under reduced pressure andpurified by removal of the excess acetic acid under high vacuum (˜0.1mmHg) to yield 26 in 99% yield. ¹H NMR (500 MHz, C₆D₆) δ 8.64 (NH) 5.88(d, J=6.3 Hz, 1H), 5.12 (t, J=7.7 Hz, 1H), 3.79 (td, J=12.5, 4.0 Hz,1H), 3.58 (ddd, J=13.1, 5.0, 2.6 Hz, 1H), 1.98-1.80 (m, 3H), 1.65 (s,3H), 1.30-1.09 (m, 7H), 0.86 (t, J=7.6 Hz, 3H). ¹³C NMR (125 MHz, C₆D₆)δ 169.0, 156.4, 131.5, 116.9, 66.7, 65.3, 33.0, 31.3, 29.4, 26.4, 22.5,20.2, 13.9. HRMS (ESI) m/z calculated for C₁₃H₂₁NO₄ [M+H⁺] 256.1544,found 256.1547.

Compound 27.

A solution of the E bicyclic methylene aziridine 14a (84.1 mg, 0.431mmol, 1.0 equiv) in 20 mL MeOH was treated with a single portion ofSc(OTf)₃ (22.8 mg, 0.0463 mmol, 0.11 equiv). The reaction mixture wasmonitored by TLC until complete, then concentrated under reducedpressure and purified via flash column chromatography (9:1 hexanes/ethylacetate-1:1 hexanes/ethyl acetate) through silica gel pre-treated with0.5% triethylamine to obtain 27 in 42% yield as a single diastereomer.¹H NMR (500 MHz, C₆D₆) δ 8.67 (NH), 5.20 (t, J=7.1 Hz, 1H), 4.07 (d,J=7.1 Hz, 1H), 3.89 (td, J=12.0, 3.6 Hz, 1H), 3.68 (ddd, J=12.0, 5.7,2.3 Hz, 1H), 3.05 (s, 3H), 2.03-1.96 (m, 1H), 1.72-1.64 (m, 2H),1.25-1.07 (m, 7H), 0.87 (t, J=6.2 Hz, 3H). ¹³C NMR (125 MHz, C₆D₆) δ156.8, 132.9, 117.1, 73.5, 65.3, 55.4, 34.1, 31.3, 29.6, 26.1, 22.5,13.9. HRMS (ESI) m/z calculated for C₁₂H₂₁NO₃ [M+H⁺] 1228.1595, found228.1607.

Compound 28.

A solution of the E bicyclic methylene aziridine 14a (76.2 mg, 0.4 mmol,1.0 equiv) in 4.5 mL CH₂Cl₂ was treated with thiophenol (70.0 μL, 0.7mmol, 1.75 equiv) at rt. The reaction mixture was stirred for 5 min,then treated with a single portion of Sc(OTf)₃ (19.2 mg, 0.04 mmol, 0.10equiv). The reaction mixture was monitored by TLC until completeconsumption of starting material, then concentrated under reducedpressure and purified via flash column chromatography (9:1 hexanes/ethylacetate-1:1 hexanes/ethyl acetate) through silica gel pre-treated with0.5% triethylamine to obtain 28 as a colorless oil in 46% yield as asingle diastereomer. ¹H NMR (500 MHz, C₆D₆) δ 7.40 (d, J=7.7 Hz, 2H,Ar), 7.01-6.94 (m, 3H, Ar), 6.97 (NH), 4.13 (t, J=4.0 Hz, 1H), 3.70-3.58(m, 2H), 3.34 (dd, J=8.3, 7.3 Hz, 1H), 1.61-1.57 (m, 2H), 1.49 (quint,J=7.4 Hz, 2H), 1.29-1.08 (m, 6H), 0.85 (t, J=7.0 Hz, 3H). ¹³C NMR (125MHz, C₆D₆) δ 157.5, 134.0, 133.4, 132.7, 128.7, 128.0, 106.7, 66.4,56.2, 32.3, 31.2, 28.5, 27.2, 22.4, 13.9. HRMS (ESI) m/z calculated forC₁₇H₂₃NO₂S [M+H⁺] 306.1523, found 306.1515.

VI. Reactions to Functionalize all Three Allene Carbons withHeteroatoms.

Compound 29.

To a solution of ice-cooled methylene aziridine 14a (72.1 mg, 0.37 mmol)in 6 mL of a 1:1 THF/H₂O mixture was added N-bromosuccinimide (72.3 mg,0.41 mmol) in one portion. The reaction mixture was warmed slowly to rtand monitored by TLC until complete consumption of starting material wasobserved. The reaction mixture was dried over Na₂SO₄ and the volatilesremoved under reduced pressure. The residue was taken up indichloromethane, washed three times with H₂O, dried over Na₂SO₄ and thesolvent removed under reduced pressure. The residue was purified bycolumn chromatography (1:1 hexanes/EtOAc) to obtain 29 as a white solidin 59% yield as a 5.5:1 mixture of diastereomers, which slowlyequilibrated in solution to give a 1.1:1 mixture of diastereomers. ¹HNMR (500 MHz, C₆D₆) δ 7.47 (s, br, 2.1H), 4.40 (isomer A, dd, J=7.1, 7.1Hz, 1H), 4.31 (isomer B, t, J=7.3, 7.3 Hz, 1.1H), 3.77 (isomer A, ddd,J=5.6, 5.6, 3.2 Hz, 1H), 3.75-3.66 (isomer A+B, m, 2.1H), 3.64 (isomerB, ddd, J=6.1, 6.1, 2.4 Hz, 1.1H), 3.46 (isomer A, ddd, J=10.3, 6.4, 4.2Hz, 1H), 3.40 (isomer B, ddd, J=10.8, 7.1, 4.2 Hz, 1.1H), 1.98-1.77(isomer A+isomer B, m, 4.4H), 1.64-1.55 (isomer A+isomer B, m, 1.2H),1.43-1.03 (isomer A+isomer B, m, 18.8H), 0.84 (isomer A+isomer B, t,J=6.9 Hz, 6.3H). ¹³C NMR (500 MHz, C₆D₆) δ 201.4, 200.8, 154.2, 154.1,64.8, 64.5, 56.9, 56.1, 49.7, 48.4, 33.6, 33.5, 31.8, 31.7, 27.5 (2carbons), 23.7, 23.6, 23.1 (2 carbons), 14.5 (2 carbons). m.p. 99-101°C. HRMS (ESI) m/z calculated for C₁₁H₁₈BrNO₃ [M+H⁺] 292.0543, found292.0548.

Stereochemical Rationale for the Initial Major Diastereomer:

One major diastereomer is produced in this reaction, but a mixture isobtained upon standing. This is not particularly surprising, as theasymmetric center of α-bromoketones is known to be quite labile. Theinitial preponderance of one diastereomer suggests that further studiesto understand the factors controlling the stereochemistry will lead tosynthetically useful reactions. A proposed mechanism involves theformation of the bromonium ion predominately on one face of the olefinof the methylene aziridine. It is unlikely that a purely S_(N)2 attackwould occur at the spiro carbon, but formation of the hemiaminal iscertainly plausible. Facile formation of the ketone would open theaziridine ring and generate the observed product. Future studies areunderway to confirm this proposed mechanism.

Compound 30.

To a solution of the E enecarbamate 26 (30.1 mg, 0.12 mmol, 1.0 equiv)dissolved in 1.0 mL THF and 1.0 mL H₂O cooled to 0° C. was addedN-bromosuccinimide (29.0 mg, 0.163 mmol, 1.4 equiv) in one portion. Thereaction mixture was warmed slowly to rt and monitored by TLC untilcomplete consumption of starting material was observed. The reactionmixture was extracted with three portions of ethyl acetate, washed withbrine, dried over magnesium sulfate, and concentrated under reducedpressure. The reside was purified via flash column chromatography (9:1hexanes/ethyl acetate to ethyl acetate) pre-treated with 0.5%triethylamine to afford 30 in 68% yield as a 2.3:1 mixture of E:Zisomers (Isomer A=E; Isomer B=Z). ¹H NMR (500 MHz, C₆D₆) δ 8.14 (IsomerA, NH), 6.66 (Isomer B, NH), 6.25 (Isomer A, d, J=6.2 Hz, 1H), 5.77(Isomer B, d, J=6.9 Hz, 0.4H), 3.75 (Isomer A, td, J=12.4, 4.1 Hz, 1H),3.57 (Isomer B, td, J=12.9, 4.1 Hz, 0.4H), 3.48-3.41 (Isomer A+B, m,1.5H), 2.54-2.48 (Isomer A, m, 1.0H), 2.44-2.37 (Isomer A+B, m, 1.4H),2.31-2.26 (Isomer B, m, 0.4H), 1.81-1.60 (Isomer A+B, m, 6H), 1.56-1.46(Isomer A+B, m, 3H), 1.41-1.33 (Isomer A+B, m, 2H), 1.29-0.95 (IsomerA+B, m, 8H), 0.87 (Isomer A, t, J=6.7 Hz, 3H), 0.83 (Isomer B, t, J=7.4Hz, 1.5H). ¹³C NMR (125 MHz, C₆D₆) δ 168.9, 168.7, 155.4, 153.6, 130.2,116.0, 112.3, 72.1, 66.9, 65.3, 64.9, 35.7, 35.1, 32.8, 31.8, 30.7,30.6, 28.4, 27.5, 22.4, 22.4, 20.1, 19.9, 13.8, 13.8. HRMS (ESI) m/zcalculated for C₁₃H₂₀NO₄Br [M+H⁺] 334.0649, found 334.0657.

Compound 31.

A solution of the E enecarbamate 26 (65.5 mg, 0.257 mmol, 1.0 equiv)dissolved in 2.0 mL THF and 2.0 mL H₂O was cooled to 0° C.N-bromosuccinimide (53.8 mg, 0.302 mmol, 1.2 equiv) was added in oneportion. After 5 min, NaBH₃CN (64.1 mg, 1.02 mmol, 4.0 equiv) was added,followed by acetic acid (400 μL, 7.0 mmol, 23 equiv) and the reactionmixture was allowed to warm to rt. The reaction was monitored by TLCuntil complete consumption of the starting material was observed (2 h).The reaction mixture was extracted with three portions of ethyl acetate,washed with brine, dried over magnesium sulfate, and concentrated underreduced pressure. The reside was purified via flash columnchromatography (4:1 hexanes/ethyl acetate to ethyl acetate) pre-treatedwith 0.5% triethylamine to afford 31 as a clear, colorless oil in 73%yield as approximately a 10:1 mixture of diastereomers. ¹H NMR (500 MHz,C₆D₆) δ 5.43 (d, J=2.5 Hz, NH), 4.93 (dd, J=3.7, 3.4 Hz, 1H), 3.82 (ddd,J=12.5, 7.7, 5.6 Hz, 1H), 3.61 (ddd, J=8.7, 6.4, 4.4 Hz, 1H), 3.52 (appdt, J=13.1, 4.1 Hz, 1H), 3.16 (dd, J=6.2, 3.9 Hz, 1H), 1.63 (s, 3H),1.17 (m, 10H), 0.84 (t, J=8.4 Hz, 3H); ¹³C NMR (125 MHz, C₆D₆) δ 168.8,157.9, 66.5, 63.3, 58.6, 56.3, 34.9, 33.4, 30.5, 26.6, 22.1, 20.0, 13.5.HRMS (ESI) m/z calculated for C₁₃H₂₂NO₄Br [M+Na]⁺ 358.0625, found358.0609.

Stereochemical Rationale for the Major Product:

Although the stereochemical relationship amongst all threeheteroatom-bearing carbons has not been conclusively proven by X-raycrystallography, the identity of the major diastereomer is rationalizedby the following observations. First, the major diastereomer appears tohave a syn relationship between the carbamate and acetate groups. Acoupling constant between the two protons a and b of about 4 Hz suggestsa dihedral angle of 70° or 110° according to the Karplus equation. Thehigh diastereoselectivity observed when an acetate group is presentsuggests the likelihood of anchimeric assistance. One proposedmechanism, as illustrated below, involves shielding of one of the facesof the enecarbamate by the acetate group. This may be due to a number offactors, including conformational stability, intramolecularhydrogen-bonding or electrostatic interactions. Nonetheless, formationof the intermediate bromonium ion then occurs on the opposite face ofthe double bond from the acetate group. Acetate-assisted opening of thebromonium ion, followed by stereoselective reduction, yields 31. Thereare several other possibilities, yet these would also be likely to giverise to the same relative stereochemistry. Studies are underway toobtain an improved understanding of the factors that control this highlystereoselective reaction.

Compound 32

(General Procedure). The allenic carbamate 13 (1.00 mmol, 1.0 equiv) and10 mL of dry CH₂Cl₂ were added to a dry 50 mL Schlenk flask. Thesolution was kept under an atmosphere of nitrogen and charged with MgO(2.60 mmol, 2.6 equiv) and Rh₂esp₂ (0.0250 mmol, 0.025 equiv). Theresulting blue-green mixture was stirred for 10 min at rt, thenPhI(OPiv)₂ or PhI(OAc)₂ (1.00 mmol, 1.0 equiv) was added and the flaskwas fitted with a reflux condenser and heated to 35° C. in an oil bathfor 1 h. Two additional portions of oxidant (2×0.51 mmol, 1.02 equiv)were added at 1 h intervals. The reaction was monitored by TLC until itwas complete, then cooled to 0° C. in an ice bath. A portion ofN-aminophthalimide (1.5 mmol, 1.5 equiv) and dry potassium carbonate(3.5 mmol, 3.5 equiv), followed by additional PhI(OAc)₂ (1.6 mmol, 1.6equiv) were added and the resulting light yellow slurry allowed to warmslowly to rt. The reaction was monitored by TLC and additional portionsof PhtNNH₂ and PhI(OAc)₂ were added as necessary to complete thereaction. A non-aqueous workup was preferred, but the products from thetandem reactions were less sensitive to water than the MAs. Thedichloromethane was removed under reduced pressure on a vacuum line, theresidue diluted with dry Et₂O and the organics decanted. The residualsalts were washed two more times with Et₂O and the volatiles removedunder reduced pressure on a vacuum line. A silica gel column was packedusing 99.5:0.5 hexanes/triethylamine, followed by flushing with fourcolumn volumes of hexanes prior to loading the sample onto the column.The residue was loaded onto the column and initially eluted using ahexanes/ethyl acetate gradient. Depending on the polarity of theproducts, 5-10% methanol was added to the eluant towards the end of thecolumn to remove any highly polar materials. Phenyl iodide eluted firstfrom the column, followed by unreacted MA (if present),N-aminophthalimide/hydrolysis products and finally the products ofnucleophilic ring-opening of the intermediate MA. The product wasobtained in 46% yield as approximately a 2.4:1 ratio of diastereomers.Major diastereomer: ¹H NMR (300 MHz, CDCl₃) δ 7.88-7.63 (Ar, 4H), 6.68(br s, 1H), 4.78 (m, 1H), 4.15 (dd, 1H, J=9.6, 4.2 Hz), 3.70 (d, 1H,J=6.6 Hz), 1.89 (s, 3H), 1.51 (d, 3H, J=7.0 Hz), 1.81-1.2 (severalsignals, 8H), 0.90 (t, 3H, J=6.5 Hz). Minor diastereomer: ¹H NMR (300MHz, CDCl₃) δ 7.88-7.63 (Ar, 4H), 6.37 (br s, 1H), 4.78 (m, 1H), 3.63(br dd, 1H, J=6.6, 6.0 Hz), 3.47 (d, 1H, J=3.3 Hz), 1.95 (s, 3H), 1.43(d, 3H, J=6.0 Hz), 1.81-1.21 (several signals, 8H), 0.90 (t, 3H, J=6.5Hz). Both diastereomers: ¹³C NMR (75 MHz, CDCl₃) δ 170.1, 168.5, 165.7,160.0, 158.9, 134.6, 134.5, 134.3, 134.2, 129.9, 123.7, 123.6, 123.5,123.2, 76.4, 74.8, 74.6, 74.3, 73.6, 62.2, 61.3, 53.1, 31.6, 31.5, 29.7,29.4, 28.9, 26.1, 26.0, 22.4, 21.3, 20.7, 20.6, 14.9, 14.0. HRMS (ESI)m/z calculated for [M+Na]⁺ 438.1636, found 438.1623.

Example 2 Stereocontrolled N,N-Aminal Synthesis Via Allene Oxidation

Chiral N,N-aminals are structural motifs found in a number ofbiologically active natural products and pharmaceuticals that exhibitpromising anti-cancer, anti-inflammatory, antiplasmodial andanticholinesterase activities. Among the molecules containing thisfunctionality are the pyrroloindoline alkaloids, the phakellin-typepyrrole-imidazole alkaloids, the lycoposerramines, as well as thechallenging synthetic targets (+)-haplophytine and stemoxazolidinone F.

The most straight-forward method to access N,N-aminals involvestreatment of a ketone or an aldehyde with an excess of amine in thepresence of an acid catalyst. Enamine formation is a competing processwhen an α hydrogen is present, however the stereochemical outcome of thereaction is difficult to control. These issues can sometimes becircumvented by the diastereoselective intramolecular addition of atethered amine to a pre-formed iminium ion (eq. 1), a process that hasbeen showcased in a number of indole alkaloid natural product syntheses.The asymmetric preparation of N,N-aminals from an unsaturated substratesuch as a tryptamine derivative (eq. 2) is much more challenging, asprotonation serves as the enantiodetermining step. Intermolecularpreparations of enantioenriched N,N-aminals are also limited, althoughAntilla and co-workers (Chem. Commun. 2007, 4477-4479) have reported theasymmetric addition of nitrogen nucleophiles to imines using a VAPOLphosphoric acid catalyst (eq. 3).

The development of new methods for the rapid and stereoselectiveintroduction of multiple heteroatoms into readily available syntheticintermediates is important for drug discovery and for improving currentsynthetic routes to known therapeutic agents. Compared tostate-of-the-art olefin oxidations, use of allene substrates offersseveral advantages, including the ability to form three newcarbon-heteroatom bonds in a single flask, increased flexibility in thechoice of heteroatoms employed and the capability of transferring asingle element of axial chirality to three new stereodefined sp³carbon-heteroatom bonds. This example describes the diastereoselectivebis-aziridination of allenes to strained 1,4-diazaspiro[2.2]pentanes(DASPs) and the transformation of these reactive intermediates to chiralN,N-aminals, resulting in the formation of four new carbon-heteroatombonds in a single reaction flask. The axial chirality of the allene canbe transferred to all four new C—X bonds in the N,N-aminal product,where X is a heteroatom, with good fidelity (eq. 4).

To gain a better understanding of the unexplored chemical behavior ofpotentially highly reactive 1,4-diazaspiro[2.2]pentanes, the scope ofintermolecular bis-aziridination of allenes was briefly examined.Treatment of 5 with PhthNNH₂ in the presence of PhI(OAc)₂ as the oxidantgave a 59% yield of the desired DASP 5a as one major diastereomer (Table2-1, entry 1). Pyramidal inversion of the aziridine nitrogens of 5a gaverise to a mixture of three invertomers in a 100:21:11 ratio. Dynamic NMRexperiments showed that only a single compound was present at rt,although a coalescence temperature could not be reached before the DASPunderwent thermal rearrangement. The phthalimido group of the terminalaziridine and the ester maintain a cis relationship in the solid state,as demonstrated by an X-ray crystal structure of 3a (see theExperimental Details section below for additional information).

TABLE 2-1 Intermolecular DASP synthesis.

entry R¹, R², R³ yield dr 1 5 H, Me, CO₂Et 59%^([a]) 5a  >9:1 2 6aC₅H₁₁, H, (CH₂)₂OTBS 65% 7a    1:1 3 6b C₅H₁₁, H, CH₂CO₂Et 73% 7b  1.6:14 6c C₅H₁₁, H, C(Me)₂CO₂Et 51% 7c, 19% 8c  1.3:1 5 6d C₄H₉, H, C₄H₉ 46%7d, 7% 8d  >9:1 6 6e Me, Me, CO₂Et 62% 7e    1:1 7 6f Me, Me, Me, Me 0%— ^([a])One major diastereomer as a mixture of invertomers.

The remaining examples in Table 2-1 summarize the effect of allenesubstitution on the yield and diastereoselectivity of DASP formation. Ingeneral, 1,3-disubstituted allene substrates (entries 2-5) gave moderateyields of the corresponding DASPs as mixtures of diastereomers, asopposed to the invertomers seen for terminal allene precursors such as 5(entry 1). Slightly better selectivity was seen when a CO₂Et group wasattached to the carbon α to the allene (entries 3-4), perhaps due tosecondary interactions of the ester with one of the NPhth groups orbetter regioselectively in the first allene aziridination. An increasein the steric bulk around the allene 6c (entry 4) also resulted in a 19%recovery of the intermediate MA 8c as a mixture of regioisomers.Eliminating a stereochemical element through the use of a symmetric1,3-disubstituted allene 6d (entry 5) yielded only one major DASPdiastereomer 7d. The reaction of a 1,1′,3-trisubstituted allene (entry6) gave a 62% yield of 7e as a 1:1 mixture of diastereomers. An attemptto use a tetrasubstituted allene 6f met with no success.

Differentiation in the electronics of the two DASP aziridines wasdifficult to achieve using a purely intermolecular aziridination of theallene substrate. The intermediate methylene aziridine was even morereactive than the allene and significant amounts of DASPs were formed.Thus, to further develop this chemistry and control the subsequentreactivity of DASPs, the electronic differentiation of the two aziridinerings using an intra/intermolecular bis-aziridination approach wasexplored. The syntheses and preliminary reactivities of an unusual classof compounds, the bicyclic methylene aziridines (MAs), obtained from theRh-catalyzed intramolecular aminations of allenes (Scheme 2-1, 1 to 2)is described above in Example 1.

Treatment of 2 with N-aminophthalimide (PhtNNH₂) as a second nitreneprecursor would be expected to form a highly strained and reactive1,4-diazaspiro[2.2]pentane 3 (Atkinson and Malpass, Tetrahedron Lett.1975, 48, 4305-4306). In contrast to traditional methods for N,N-aminalformation, the key intermediate 3 allows for the introduction ofadditional functionality into the molecule via aziridine ring-opening.The differentiation in the ring strain and electronic environment of thetwo aziridines of 3 would be expected to promote regioselectivenucleophilic ring-opening of the more strained aziridine to yield theN,N-aminal 4.

A carbamate group was utilized as a robust and atom-economical nitrogenprotecting group for the first ring formed through intramolecular alleneaziridination. The resulting [6,3]-bicyclic MAs were then treated withPhtNNH₂ in the presence of PhIO to form the corresponding DASPs inmoderate to good yields (Table 2-2).

TABLE 2-2 The preparation of electronically differentiated1,4-diazaspiro[2.2]pentane aminals.

  58% (65%)^([a]) 9a (1)

  10a 72% (2)

  11a 33%^([b]) (3)

  12a 79% (4)

  13a 75% (5)

  14a 42% (58%)^([a,b]) (6)

  15a 66% (71%)^([b]) (7)

  16a 40% (56%)^([c]) (8)

  17a 46% (9) ^([a])Yield based on recovered starting material.^([b])The starting material was the Z methylene aziridine. ^([c])Yieldbased on the E methylene aziridine.

Substitution in the carbamate linker did not greatly affect the secondaziridination event, as both the unsubstituted 9 and the gem-dimethylsubstituted 10 gave similar yields of 9a and 10a (entries 1 and 2).However, the olefin geometry of the substrate MA was important. The Eisomer 9 gave a 72% yield of the DASP, while the Z isomer 11 gave only a33% yield and reacted much more slowly. Examination of the X-ray crystalstructure of 10a (FIG. 3) indicated that the second aziridinationoccurred on the face of the MA opposite that of the first aziridine, asmight be expected on steric grounds. The nitrene transfer appears to bestereoselective, as only one diastereomer was observed by ¹H NMR. The Estereochemistry from the intermediate MA 10 translated into a synrelationship between the C₅H₁₁ side chain and the C—C bond of thecentral aziridine in 10a. Conversely, the DASP product 11a from the Z MAisomer 11 indicated the C₅H₁₁ chain and the C—C bond of the centralaziridine are in an anti relationship. This forces a steric clashbetween the phthalimide group of the aziridine and the alkyl side chain,which may explain the slower reaction rate and lower yields as comparedto the E methylene aziridines (Table 2-2, entries 3 and 8). Theseresults also indicate that either the second aziridination occurs via asinglet nitrene, or the intermediate generated from addition of atriplet nitrene does not have time to rotate before ring closure to theDASP.

The stereoselective nature of the DASP formation ensured that the axialchirality from an enantioenriched allene could be transferred to theintermediate MA, and subsequently to the DASP, with good fidelity(Scheme 2-3). The er of the product 21 could be increased to 96:4 afterone recrystallization. The plethora of new methods available foraccessing enantioenriched allenes makes this approach a convenient wayto access synthetic motifs containing three stereodefined and contiguouscarbon-heteroatom bonds from simple precursors (for selected reviews onthe synthesis of enantioenriched allenes, see M. Ogasawara, Tetrahedron:Asymmetry 2009, 20, 259; and Kim and Williams, Curr. Opin. Drug Disc.2006, 11, 870).

Another advantage of utilizing 1,4-diazaspiro[2.2]pentanes as reactiveintermediates is the ability to further manipulate the molecule whilestill maintaining the N,N-aminal functionality. As illustrated in Table2-3, weak nucleophiles gave almost exclusive ring-opening at theinternal aziridine. For example, acetic acid opened the DASP 9a in 95%yield to give one regioisomer 22 (Table 2-3, entry 1).

TABLE 2-3 Nucleophilic ring-opening of tricyclic DASPs.

  AcOH, 95% 22 (1)

  AcOH, 65% 23 (2)

  AcOH, 68% 24 (3)

  AcOH, 85%^([a]) 25 (4)

  PivOH, 80% 26 (5)

  LiCl, 84% 27 (6)

  TMSCl, 93% 28 (7)

  AcSH, 82% 29 (8)

  TMSN₃, 74% 30 (9)

  48%^([b]) 31 (10) ^([a])The substrate was the DASP generated fromaziridination of the Z methylene aziridine. ^([b])The remainder of themass balance was unreacted starting material.

The gem-dimethyl DASP 10a also gave only one product 23 (entry 2). ForDASPs derived from Z-methylene aziridines (entry 4), reaction withacetic acid gave even better yields of the ring-opened product 25,perhaps due to less steric hindrance during the approach of thenucleophile. However, even the bulky pivalic acid gave good yields ofthe N,N-aminal 26 (entry 5). Chloride was also a good nucleophile,opening both DASPs 9a and 10a in excellent yields using either LiCl orTMSCl as the halogen source (entries 6 and 7). A new C—S bond could beintroduced into the N,N-aminal by treatment of 10a with thioacetic acidto give 29 (entry 8) in 82% yield. Stronger nucleophiles, includingcyanide and azide (entries 9 and 10) successfully opened the DASPs withgood regioselectivity at the internal aziridine carbon. However, thebasicity of the nucleophile and/or the increased acidity of the proton αto the newly introduced group promoted deprotonation and subsequentring-opening of the Pht-protected aziridine to give the unusualheteroatom-substituted olefins 30 and 31.

Finally, the allenic carbamate substrates can be converted directly tofunctionalized N,N-aminals in one flask as a single diastereomer (Table2-4). Four new carbon-heteroatom bonds and three chiral centers aregenerated in a stereoselective fashion using operationally simpleprocedures under mild reaction conditions.

TABLE 2-4 One-pot stereocontrolled synthesis of N,N-aminals fromallenes.

  23 AcOH, 46% (33%)^([a]) (1)

  28 TMSCl, 53% (46%)^([a]) (2)

  29 AcsH, 48% (42%)^([a]) (3) ^([a])Combined yield of the threeindividual steps. The yields were also increased significantly in theone-pot reaction; for example, the yield of 23 (Table 2-4, entry 1)improved to 46%, compared to 33% for the three-step process.

Accordingly, allene aziridination can be used as a key step for thepreparation of stereodefined N,N-spiroaminals. The axial chirality ofthe substrate can be translated into three new heteroatom-bearingasymmetric centers in the final product. Allenic carbamates can alsoundergo an efficient and stereocontrolled one-pot amination to yieldfunctionalized N,N-aminals. This efficient transformation generates fournew carbon-heteroatom bonds in a single flask, where the axial chiralityof the allene can be translated into the product with good fidelity.

General Procedure for Tandem Allene Oxidations to N,N-Aminals.

A 50 mL flame-dried round bottom flask was charged with 3 Å molecularsieves, followed by Rh₂esp₂ (0.041 mmol, 0.025 equiv). The alleniccarbamate (1.6 mmol, 1.0 equiv) in 15 mL of dry CH₂Cl₂ was added to thereaction flask. The resulting blue-green mixture was stirred for 10 minat rt under a flow of nitrogen, then iodosobenzene (4.1 mmol, 2.5 equiv)was added in one portion. The reaction was monitored by TLC until it wascomplete, then cooled to 0° C. in an ice bath. A portion ofN-aminophthalimide (3.1 mmol, 1.9 equiv) and dry potassium carbonate(6.4 mmol, 4.0 equiv), followed by additional oxidant (3.0 mmol, 1.9equiv) were added and the resulting light yellow slurry allowed to warmslowly to rt. The reaction mixture was monitored by TLC and additionalportions of PhtNNH₂ and oxidant were added until no further conversionto the 1,4-diazaspiro[2.2]pentane was noted. The desired nucleophile wasthen added (15.0 equiv) and the reaction stirred at rt until complete.The reaction mixture was passed through a plug of silica gel to removesolids using first Et₂O, then EtOAc to flush the plug. The solvents wereremoved under reduced pressure and the residue was purified via silicagel column chromatography (hexanes/ethyl acetate gradient). Phenyliodide eluted first from the column, followed by the Rh catalyst,unreacted methylene aziridine (if present), unreacted1,4-diazaspiro[2.2]pentane(s) (if present), products of the hydrolysisof the excess N-aminophthalimide and finally, the desired N,N-aminalproduct as a single diastereomer.

Experimental Details.

See the General Experimental Information section of Example 1 fordetails regarding materials and instrumentation, and for the preparationof allene substrates.

I. Intermolecular Synthesis of 1,4-Diazaspiro[2.2]pentanes.

General Procedure.

A solution of the allene (1.0 mmol, 1.0 equiv) in 10 mL of drydichloromethane was treated with N-aminophthalimide (2.8 mmol, 2.8equiv) and dry potassium carbonate (7.0 mmol, 7.0 equiv), followed byPhIO (3.0 mmol, 3.0 equiv). The resulting light yellow slurry wasstirred at rt for 2 h, during which time the yellow color darkened.Additional portions of N-aminophthalimide (1.0 mmol, 1.0 equiv) and PhIO(1.0 mmol, 1.0 equiv) were added if necessary and the reaction monitoredby TLC until no starting material remained. If the DASP product wassensitive to ring-opening by acetate, the reaction could be stoppedprior to completion and the allene starting material recovered. Anon-aqueous workup was preferred, as many of the DASPs were sensitive towater. The salts were filtered off and washed with several smallportions of dry dichloromethane. The volatiles were removed underreduced pressure either on a vacuum line or using a rotary evaporatorwith the water bath kept at rt or below. For less reactive DASPs, thereaction mixture was diluted with water and the aqueous layer quicklyextracted three times with portions of dichloromethane. The combinedorganics were washed with brine, dried over sodium sulfate and thevolatiles removed under reduced pressure. The residue was loaded onto asilica gel column packed with hexanes and eluted using a hexanes/ethylacetate gradient. For sensitive DASPs, the column was pre-treated with a99.5:0.5 mixture of hexanes/triethylamine, then further eluted with 4column volumes of hexanes before loading the column. In most cases,phenyl iodide eluted first from the column, followed by unreacted allene(if present), any intermediate methylene aziridines, then the desired1,4-diazaspiro[2.2]pentane(s) and finally, N-aminophthalimide and itshydrolysis products. The order of elution of DASP and N-aminophthalimidewas variable depending on the polarity of the product.

Compound 5a.

The light yellow solid was obtained in 59% yield after columnchromatography (hexanes/EtOAc gradient). The compound was furtherrecrystallized from EtOAc/CHCl₃ to obtain crystals suitable for X-raycrystallography. Proton NMR showed approximately a 100:22:11 mixture ofinvertomers at rt. The identity of the invertomers was not established,as variable temperature NMR studies indicated only a single diastereomerwas present. Major invertomer: ¹H NMR (600 MHz, CDCl₃) δ 7.79-7.65 (Ar,8H), 4.15 (d, 1H, J=1.2 Hz), 3.97 (m, 1H), 3.89 (m, 1H), 3.63 (d, 1H,J=1.2 Hz), 1.78 (s, 3H), 0.94 (t, 3H, J=7.3 Hz). Minor invertomer: ¹HNMR (600 MHz, CDCl₃) δ 7.79-7.65 (Ar, 8H), 4.63 (d, 1H, J=3.5 Hz), 4.34(m, 2H), 3.29 (d, 1H, J=3.5 Hz), 1.59 (s, 3H), 1.32 (t, 3H, J=6.4 Hz).Mixture of invertomers: ¹³C NMR (150 MHz, CDCl₃) δ 167.4, 165.9, 165.8,164.9, 134.5, 134.4, 134.3, 134.0, 133.9, 130.5, 130.3, 130.2, 129.7,123.4, 123.3, 123.2, 62.8, 62.4, 62.1, 52.9, 35.5, 35.2, 14.1, 13.7,13.5, 12.8. HRMS (ESI) m/z calculated for [M+Na]⁺ 469.1119, found469.1130.

Compound 7a.

The light yellow solid was obtained in 65% yield after columnchromatography as approximately a 1:1 mixture of diastereomers. Bothdiastereomers: ¹H NMR (500 MHz, CDCl₃) δ 7.83-7.60 (Ar, 8H total), 4.29(overlapping signals, 0.8H total), 4.04 (m, 0.5H total), 3.87(overlapping signals, 1.9H total), 3.68 (dd, 0.8H total, J=6.5, 6.5 Hz),2.67 (m, 0.5H total), 2.44 (m, 1.0H total), 2.20 (overlapping signals,1.5H total), 1.88 (m, 1.0H total), 1.78-1.60 (overlapping signals, 2.5Htotal), 1.40-1.28 (br m, 3.5H total), 0.88-0.80 (2 t, 3H total),0.82-0.72 (2 s, 9H total), 0.08 and 0.06 (2 s, 3H total), −0.08 and−0.09 (2 s, 3H total). ¹³C NMR (125 MHz, CDCl₃) δ 167.9, 165.5, 165.4,165.2, 165.1, 134.4, 134.2, 134.1, 134.0, 133.8, 132.6, 130.5, 130.4,130.3, 123.5, 123.1, 123.0, 70.5, 69.9, 60.5, 60.2, 50.3, 47.4, 47.3,45.6, 34.1, 31.8, 31.7, 31.6, 30.6, 28.1, 26.3, 26.0, 25.9, 25.7, 25.6,22.5, 22.4, 18.2, 18.1, 14.0, 13.9, −5.4 (2), −5.5, −5.6. HRMS (ESI) m/zcalculated for [M+Na]⁺ 611.2661, found 611.2637.

Compound 7b.

The light yellow solid was obtained in 73% yield as a 1.6:1 mixture ofdiastereomers following column chromatography. Major diastereomer: ¹HNMR (500 MHz, CDCl₃) δ 7.90-7.64 (Ar, 8H), 4.37 (dd, 1H, J=7.1, 5.8 Hz),4.23 (q, 2H, J=7.4 Hz), 4.01 (dd, 1H, J=8.3, 5.2 Hz), 3.55 (dd, 1H,J=17.5, Hz), 3.49 (dd, 1H, J=17.5, 8.0 Hz), 1.91 (m, overlappingsignals, 2H), 1.69-1.44 (m, overlapping signals, 6H), 1.31 (t, 3H, J=7.2Hz), 0.85 (t, 3H, J=7.2 Hz). Minor diastereomer: ¹H NMR (500 MHz, CDCl₃)δ 7.9-7.64 (Ar, 8H), 4.55 (dd, 1H, J=8.5, 5.5 Hz), 4.05 (dq, 2H, J=7.2,1.3 Hz), 3.80 (dd, 1H, J=6.3, 6.3 Hz), 3.30 (dd, 1H, J=16.9, 5.5 Hz),2.58 (dd, 1H, J=17.1, 8.7 Hz), 2.45 (m, 1H), 2.20 (m, 1H), 1.69-1.44 (brm, 6H), 1.08 (t, 3H, J=7.2 Hz), 0.94 (t, 3H, J=7.2 Hz). Bothdiastereomers: ¹³C NMR (125 MHz, CDCl₃) δ 170.6, 169.5, 167.9, 165.4,165.3, 165.2, 165.0, 163.4, 135.1, 134.3, 134.2, 134.1, 133.9, 132.6,130.5, 130.2, 130.0, 124.4, 123.6, 123.5, 123.3, 123.1, 123.0, 69.6,69.5, 60.9 (2), 49.8, 48.1, 45.2, 43.0, 35.9, 33.6, 31.7, 31.6, 30.2,28.2, 26.3, 25.7, 22.5, 22.4, 14.2, 14.0, 13.9 (2). HRMS (ESI) m/zcalculated for [M+Na]⁺ 539.1902, found 539.1906.

Compound 7c.

The compound was obtained in 51% yield as a light yellow solid as anapparent 1.3:1 mixture of diastereomers (or possibly invertomers). A 19%yield of a mixture of the intermediate methylene aziridines 6c was alsoobtained. ¹H NMR (500 MHz, CDCl₃) δ 8.11-7.59 (Ar, 8H), 4.58 and 2.69 (2s in a ratio of 1.3:1, 1H total), 3.91 and 3.84 (q, J=7.2 Hz and app dd,J=7.6, 5.9 Hz, 2H), 2.52 (m, 1H), 2.22 (m, 1H), 2.08 (s, 1H), 1.79 (m,2H total), 1.61 (s, 3H), 1.51-1.37 (overlapping signals, 4H total), 1.14(s, 3H), 0.94 (t, 3H, J=7.3 Hz), 0.89 (t, 3H, J=7.3 Hz). ¹³C NMR (125MHz, CDCl₃) δ 175.2, 168.0, 165.4, 165.2, 136.0, 135.5, 135.1, 134.3,134.1, 133.8, 130.5, 130.3, 124.5, 123.6, 123.1 (2), 68.8, 60.9, 50.8,50.7, 42.9, 31.9, 28.2, 26.4, 23.9, 22.6, 20.7, 14.1, 14.0. HRMS (ESI)m/z calculated for [M+N+H₂O]⁺ 585.2320, found 585.2307. The methyleneaziridine 8c was also isolated as a mixture of regioisomers. HRMS (ESI)m/z calculated for [M+Na]⁺ 407.1942, found 407.1932.

Compound 7d.

The desired product was obtained in 46% yield as one major diastereomer(dr>9:1 by ¹H NMR). ¹H NMR (500 MHz, CDCl₃) δ 7.96-7.62 (Ar, 8H), 4.25(dd, 1H, J=6.5, 6.2 Hz), 3.65 (t, 1H, J=6.9 Hz), 2.46 (m, 1H), 2.21 (m,1H), 1.75-1.34 (several overlapping signals, 10H), 0.96 (t, 3H, J=7.5Hz), 0.86 (t, 3H, J=7.5 Hz). ¹³C NMR (125 MHz, CDCl₃) δ 165.4, 165.2,135.9, 134.5, 134.2, 134.1, 130.5, 130.2, 125.6, 123.4, 123.0, 122.9,70.4, 49.8, 47.2, 30.3, 28.8, 27.8, 27.6, 22.5, 22.4, 13.8, 13.7. HRMS(ESI) m/z calculated for [M+Na]⁺ 495.2003, found 495.1995.

Compound 8d.

The methylene aziridine was obtained in 7% yield. ¹H NMR (300 MHz,CDCl₃) δ 7.78-7.63 (Ar, 4H), 6.23 (ddd, 1H, J=7.4, 7.2, 1.9 Hz), 3.36(dd, 1H, J=5.4, 5.3 Hz), 2.15 (2 d, 2H, J=7.3 Hz), 1.81-1.58 (m, 2H),1.48-1.20 (several signals, 8H), 0.92 (t, 3H, J=7.2 Hz), 0.87 (t, 3H,J=7.2 Hz). ¹³C NMR (75 MHz, CDCl₃) δ 165.2, 134.3, 133.9, 131.5, 130.6,123.5, 122.9, 113.3, 49.5, 31.6, 31.4, 28.8, 28.5, 22.6, 22.2, 13.9,13.8. HRMS (ESI) m/z calculated for [M+H]⁺ 313.1911, found 313.1914.

Compound 7e.

The DASPs were obtained in 62% yield as approximately a 1:1 mixture ofdiastereomers. Less polar diastereomer: ¹H NMR (500 MHz, CDCl₃) δ7.90-7.67 (Ar, 8H), 4.18 (m, 1H), 3.78 (m, 1H), 3.64 (m, 1H), 1.89 (s,3H), 1.81 (d, 3H, J=4.5 Hz), 0.87 (t, 3H, J=7.4 Hz). ¹³C NMR (125 MHz,CDCl₃) δ 167.9, 166.0, 165.3, 164.5, 135.5, 134.3, 134.2, 133.8, 132.7,130.8, 130.1, 129.8, 124.7, 123.9, 123.6, 123.1, 123.0, 68.0, 62.1,51.8, 39.4, 18.5, 13.5, 13.2. HRMS (ESI) m/z calculated for [M+Na]⁺483.1276, found 483.1269. More polar diastereomer: ¹H NMR (600 MHz,CDCl₃) δ 8.04-7.81 (Ar, 8H), 4.89 (q, 1H, J=5.7 Hz), 4.89 (m, 2H), 1.75(s, 3H), 1.66 (d, 3H, J=5.9 Hz), 1.37 (t, 3H, J=7.6 Hz). ¹³C NMR (150MHz, CDCl₃) δ 168.0, 167.8, 165.8, 165.6, 161.5, 135.5, 134.4, 134.3,133.9, 132.7, 130.4, 130.1, 124.7, 123.9, 123.6, 123.4, 123.1, 66.6,62.4, 62.1, 52.6, 44.1, 14.8, 14.1, 12.8. HRMS (ESI) m/z calculated for[M+Na]⁺ 483.1276, found 483.1270.

II. Differentially Protected 1,4-Diazaspiro[2.2]pentanes

Precursor for Compound 14.

Chlorosulfonyl isocyanate (10.8 mmol, 1.5 equiv) was dissolved in dryCH₂Cl₂ (25 mL) and placed in an ice bath. The homo-allenic alcohol (7.2mmol, 1 equiv) was then added slowly, and once the addition was completethe ice bath was removed and stirred at rt until the starting materialwas consumed by TLC. The reaction was then placed in an ice bath and THF(6 mL) and water (3 mL) were added to the reaction. The vessel wasfitted with a reflux condenser and refluxed until TLC indicated thereaction was complete. Brine (50 mL) was added to the reaction mixtureand the solution was extracted with CH₂Cl₂ (2×50 mL), dried with Mg₂SO₄,and the solvents removed under reduced pressure. The residue wassubjected to silica gel chromatography (0 to 50% EtOAc in hexanesgradient increased in increments of 10%) to give the product in 87%yield. ¹H NMR (300 MHz, CDCl₃) δ 5.34 (m, 1H), 4.83 (br, 2H), 4.16 (q,J=7.3 Hz, 2H), 3.86 (s, 2H), 3.02 (dd, J=7.0, 2.8 Hz, 2H), 1.27 (t,J=7.3 Hz, 3H), 1.05 (s, 6H). ¹³C NMR (75.5 MHz, CDCl₃) δ 203.8, 171.73,157.3, 99.7, 86.5, 72.8, 61.0, 35.8, 35.4, 25.0, 24.8, 14.4. HRMS (ESI)m/z calculated for [M+Na]⁺ 264.1207, found 264.1214.

Compound 14.

Dry CH₂Cl₂ (20 mL) was added to a flask that containing 4 Å molecularsieves (1.5 g) and Rh₂(esp)₂ (0.062 mmol, 0.03 equiv). The materialprepared above (2.07 mmol, 1 equiv) was added and the reaction mixturewas stirred for 10 min. PhIO (4.14 mmol, 2 equiv) was then added in oneportion and the reaction was stirred vigorously until the startingmaterial was consumed by TLC. The mixture was filtered through a silicagel pad and washed several times with EtOAc. The filtrate was thenconcentrated under reduced pressure. Crude NMR indicated a ratio of1:2.8 of the E:Z olefin isomers. The crude material was purified bysilica gel chromatography (the column was pre-treated with 1%triethylamine in hexanes). A gradient of 0% to 20% EtOAc in hexanes wasused, increasing the more polar component by increments of 10%. Thecolumn was eluted with 80/20 hexanes/ethyl acetate until the green bandcorresponding to Rh₂(esp)₂ was collected. The polarity of the eluant wasthen increased to 20% ethyl acetate and slowly increased to 50% EtOAc inhexanes to give 14 in 86% yield as a 36% yield of a mixture of E:Z and50% isolated as the pure Z isomer. Z isomer: ¹H NMR (300 MHz, C₆D₆) δ5.40 (t, J=7.4 Hz, 1H), 3.91 (q, J=7.2 Hz, 2H), 3.65 (dd, J=18.1, 7.2Hz, 1H), 3.55 (dd J=18.1 Hz, 1H), 3.42 (d, J=10.6 Hz, 1H), 3.13 (d,J=10.6 Hz, 1H), 2.47 (s, 1H), 0.91 (t, J=7.2 Hz, 3H), 0.49 (s, 3H), 0.37(s, 3H). ¹³C NMR (125 MHz, C₆D₆) δ 171.3, 154.8, 126.9, 97.3, 60.9,49.0, 33.1, 28.9, 23.5, 20.6, 14.5. HRMS (ESI) m/z calculated for[M+Na]⁺ 262.1050, found 262.1050.

General Procedure.

The bicyclic methylene aziridines 9-16 and 17 were prepared as describedin Example 1 (see also Grigg et al., Tetrahedron 2011, 67, 4318). Ifnecessary, the E and Z bicyclic methylene aziridines were separated bycolumn chromatography before initiating the DASP formation. A solutionof the methylene aziridine (1.0 mmol, 1.0 equiv) in 10 mL of drydichloromethane was cooled to 0° C. and treated with N-aminophthalimide(1.5 mmol, 1.5 equiv) and dry potassium carbonate (3.5 mmol, 3.5 equiv),followed by PhI(OAc)₂ or PhIO as the oxidant (1.6 mmol, 1.6 equiv). Theresulting light yellow slurry was allowed to warm slowly to rt andmonitored carefully by TLC. In some cases, the DASP product wassensitive to ring-opening by acetate and it was best to stop thereaction when conversion of the methylene aziridine to the DASP stalled.When reaction was complete, the dichloromethane was removed underreduced pressure on a vacuum line, the residue diluted with dry Et₂O andthe organics decanted. The residual salts were washed two more timeswith Et₂O and the volatiles removed under reduced pressure on a vacuumline. A silica gel column was packed using 99.5:0.5hexanes/triethylamine, followed by flushing with four column volumes ofhexanes prior to loading the sample onto the column to improve theseparation and prevent the decomposition of sensitive DASPs. The residuewas loaded onto the column and eluted using a hexanes/ethyl acetategradient. Phenyl iodide eluted first from the column, followed byunreacted MA (if present), then the desired1,4-diazaspiro[2.2]pentane(s) and finally, N-aminophthalimide/hydrolysisproducts and/or products arising from DASP ring-opening. The DASPs werestored in a freezer at −20° C. It was best to run NMRs in deuteratedbenzene if the sample was to be recovered, as any residual acid in theCDCl₃ caused decomposition of the product.

Compound 9a.

The E methylene aziridine 9 was utilized as the starting material. Theproduct was obtained in 58% yield after column chromatography as asingle diastereomer; the yield based on recovered starting material was65%. ¹H NMR (600 MHz, CDCl₃) δ 7.75-7.65 (Ar, 4H), 4.56 (dd, 1H, J=11.0,1.2 Hz), 4.46 (dd, 1H, J=5.4, 4.8 Hz), 3.93 (2 overlapping signals, 2H),2.46 (m, 1H), 2.03-1.08 (several signals, 9H), 0.86 (t, 3H, J=7.2 Hz).¹³C NMR (150 MHz, CDCl₃) δ 165.3, 157.7, 134.3, 130.8, 123.5, 68.8,66.9, 45.9, 42.2, 31.8, 29.6, 26.1, 22.8, 22.7, 14.2. ¹H NMR (500 MHz,C₆D₆) δ 7.25 (Ar, 2H), 6.71 (Ar, 2H), 4.28 (dd, 1H, J=5.9, 5.9 Hz),3.52-3.46 (2 overlapping signals, 2H), 3.36 (ddd, 1H, J=10.9, 4.0, 1.9Hz), 1.66-1.60 (overlapping signals, 4H total), 1.39-1.28 (br m, 4Htotal), 1.05 (dd, 1H, J=14.0, 6.5 Hz), 0.9 (t, 3H, J=6.5 Hz), 0.8(overlapping m, 1H). ¹³C NMR (125 MHz, C₆D₆) δ 165.1, 157.1, 133.4,130.9, 122.8, 68.0, 67.0, 45.5, 41.9, 31.9, 29.5, 26.2, 22.8, 22.3,14.2. HRMS (ESI) m/z calculated for [M+Na]⁺ 378.1425, found 378.1421.

Compound 10a.

The product was obtained as a single diastereomer in 72% yield usingPhIO as the oxidant and the E methylene aziridine 10 as the substrate.¹H NMR (500 MHz, CDCl₃) δ 7.74-7.65 (Ar, 4H), 4.34 (d, 1H, J=10.6 Hz),4.11 (dd, 1H, J=9.2, 3.5 Hz), 3.79 (d, 1H, J=11.3 Hz), 3.66 (s, 1H),1.92 (m, 1H), 1.86-1.79 (br m, 2H), 1.58-1.22 (overlapping signals, 5Htotal), 1.29 (s, 3H), 0.93 (s, 3H), 0.90 (t, 3H, J=7.2 Hz). ¹³C NMR (125MHz, CDCl₃) δ 165.2, 157.5, 134.1, 130.5, 123.2, 78.0, 65.0, 51.1, 46.0,31.6, 31.2, 29.6, 25.8, 24.0, 22.5, 21.0, 14.0. HRMS (ESI) m/zcalculated for [M+H]⁺ 384.1918, found 384.1926.

Compound 11a.

The compound was obtained in 33% yield as a single diastereomer usingPhIO as the oxidant and the Z methylene aziridine 11 as the substrate.The remainder of the mass balance was unreacted starting material, butthe addition of additional aliquots of PhtNNH₂ and PhIO did not push thereaction to completion. ¹H NMR (500 MHz, CDCl₃) δ 7.84-7.72 (Ar, 4H),4.31 (d, J=12.0 Hz, 1H), 3.87-3.83 (m(overlapping signals), 2H), 3.33(s, 1H), 2.18-1.99 (m, 2H), 1.77-1.59 (m, 2H), 1.43-1.33 (m, 4H),1.26-1.22 (m(overlapping signals), 4H), 1.05 (s, 3H), 0.90 (t, J=7.3 Hz,3H). ¹³C NMR (125 MHz, CDCl₃) δ 165.6, 155.8, 134.4, 130.2, 123.4, 77.6,63.3, 48.7, 48.6, 31.5, 29.4, 29.2, 26.7, 24.0, 22.4, 19.9, 14.0. HRMS(ESI) m/z calculated for [M+Na]⁺ 406.1738; found 406.1744.

Compound 12a.

The product was obtained in 79% yield. ¹H NMR (500 MHz, CDCl₃) δ7.77-7.67 (Ar, 4H), 4.60 (ddd, J=12.8, 11.5, 2.1 Hz, 1H), 4.40 (ddd,J=10.6, 4.7, 1.7 Hz, 1H), 3.97 (overlapping signals, 2H total), 2.50(dddd, J=14.9, 6.8, 2.6, 2.1 Hz, 1H), 1.72 (m, 1H), 1.14 (s, 9H). ¹³CNMR (125 MHz, CDCl₃) δ 165.1, 157.5, 134.0, 130.5, 123.1, 68.4, 65.5,53.6, 42.2, 31.3, 27.1, 23.8. HRMS (ESI) m/z calculated for C₁₈H₁₉N₃O₄[M+H⁺] 342.1449, found 342.1451.

Compound 13a.

The product was obtained in 75% yield. ¹H NMR (500 MHz, CDCl₃) δ7.80-7.68 (Ar, 4H), 7.33-7.19 (Ar, 5H), 4.50 (ddd, J=12.1, 10.9, 2.5 Hz,1H), 4.25 (ddd, J=10.5, 4.0, 2.2 Hz, 1H), 4.00 (dd, J=6.2, 6.2 Hz, 1H),3.84 (dd, J=8.7, 7.1 Hz, 1H), 3.05 (m, 2H), 2.19 (overlapping signals,3H total), 1.09 (m, 1H). ¹³C NMR (125 MHz, CDCl₃) δ 165.1, 157.2, 141.0,134.1, 130.5, 128.7, 128.5, 126.2, 123.2, 68.5, 66.5, 45.4, 41.8, 32.7,31.8, 21.6. HRMS (ESI) m/z calculated for C₂₂H₁₉N₃O₄ [M+H⁺] 390.1449,found 390.1463.

Compound 14a.

The compound was obtained in 42% yield as a single diastereomer usingPhIO as the oxidant and the Z methylene aziridine 14 as the substrate.The remainder of the mass balance was unreacted starting material andthe yield based on recovered starting material was 58%. ¹H NMR (300 MHz,CDCl₃) δ 7.82 (m, 2H), 7.75 (m, 2H), 4.33 (d, J=10.5 Hz, 1H), 4.26 (t,J=6.6 Hz, 1H), 4.19 (q, J=7.0 Hz, 2H), 3.88 (d, J=10.5 Hz, 1H), 3.38 (s,1H), 3.35 (dd, J=18.0, 6.6 Hz, 1H), 3.12 (dd, J=18.0, 6.6 Hz, 1H) 1.27(s, 3H), 1.27 (t, J=7.0 Hz, 3H), 1.16 (s, 3H). ¹³C NMR (75.5 MHz, CDCl₃)δ 170.8, 165.7, 156.3, 134.7, 130.3, 123.7, 78.1, 62.2, 61.3, 49.5,43.4, 34.8, 29.8, 24.4, 20.1, 14.3. HRMS (ESI) m/z calculated for[M+Na]⁺ 422.1323, found 422.1323.

Compound 15a.

The product was obtained in 66% isolated yield and 71% yield based onrecovered and unreacted Z methylene aziridine. ¹H NMR (500 MHz, CDCl₃) δ7.78-7.67 (Ar, 4H), 4.77 (m, 1H), 3.94 (dd, J=7.0, 4.4 Hz, 1H), 3.86(dd, J=9.3, 7.0 Hz, 1H), 2.45 (ddd, J=14.4, 6.0, 2.1 Hz, 1H), 1.95-1.88(m, 1H), 1.78-1.67 (overlapping signals, 3H total), 1.42-1.27 (m, 8H),0.92 (t, J=6.5 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 165.0, 157.9, 134.0,130.5, 123.1, 76.7, 66.9, 45.5, 41.4, 31.5, 29.4, 29.2, 25.8, 22.4,20.6, 13.9. HRMS (ESI) m/z calculated for C₂₀H₂₃N₃O₄ [M+Na⁺] 392.1581,found 392.1586.

Compound 16a.

The product was obtained in 40% isolated yield and 56% yield based onunreacted Z methylene aziridine. ¹H NMR (500 MHz, CDCl₃) δ 7.78-7.67(Ar, 4H), 3.93 (dd, J=7.8, 4.2 Hz, 1H), 3.83 (dd, J=9.1, 6.8 Hz, 1H),2.31 (dd, J=14.9, 7.1 Hz, 1H), 1.94-1.89 (m, 1H), 1.73-1.67 (m, 3H),1.64 (s, 3H), 1.58-1.20 (m, 8H), 0.92 (t, J=6.8 Hz, 3H). ¹³C NMR (125MHz, CDCl₃) δ 167.7, 160.5, 136.7, 133.3, 125.9, 87.2, 70.8, 48.2, 42.7,35.6, 34.3, 32.4, 32.0, 32.0, 28.6, 27.8, 25.1, 16.7. HRMS (ESI) m/zcalculated for C₂₁H₂₅N₃O₄ [M+Na⁺] 406.1738, found 406.1730.

Compound 17a.

The product was obtained in 46% yield. ¹H NMR (500 MHz, CDCl₃) δ7.78-7.67 (Ar, 4H), 4.59 (ddd, J=14.2, 11.4, 1.8 Hz, 1H), 4.38 (ddd,J=11.4, 3.8, 2.6 Hz, 1H), 3.96 (dd, J=7.0, 4.6 Hz, 1H), 2.14 (ddd,J=15.0, 3.4, 2.0 Hz, 1H), 2.00 (s, 3H), 1.95-1.90 (m, 1H), 1.74-1.65 (m,4H), 1.42-1.34 (m, 4H), 0.92 (t, J=7.0 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃)δ 165.3, 158.0, 134.0, 130.4, 123.1, 71.3, 67.4, 48.8, 46.1, 31.6, 29.3,29.3, 25.7, 22.4, 18.2, 13.9. HRMS (ESI) m/z calculated for C₂₀H₂₃N₃O₄[M+Na⁺] 392.1581, found 392.1570.

Compound 21.

The enantioenriched propargyl alcohol 18 was prepared according toliterature procedure (Larock and Babu, Tetrahedron 1987, 43, 2013). Thesame procedure previously reported for the synthesis of racemic 21 wasused to prepare the enantioenriched sample. High-pressure liquidchromatography (HPLC) analyses were performed at 224 and 254 nm usingShimadzu HPLC, Model LC-20AB. An AD-H column (4.6 μm diameter×258 mm) ata temperature of 40° C. was employed, using a flow rate of 1 mL/min anda gradient starting at 10% isopropanol in hexanes for 10 min andincreasing to 30% isopropanol in hexanes. The eluant was then held at30% isopropanol in hexanes until the run was completed. For therecrystallized 21, the HPLC run was started at 5% isopropanol inhexanes.

III. Reactions of 1,4-Diazaspiro[2.2]pentanes.

General Procedure for Acetic Acid DASP Ring Openings:

The DASP was dissolved in enough THF to prepare a 0.1 M solution andcooled to 0° C. Glacial acetic acid (50.0 equivalents) was addeddropwise to the reaction mixture over 2 min, ensuring that the reactiontemperature remained at 0° C. The reaction was warmed to roomtemperature and monitored by TLC until complete (3-10 h). Afterconsumption of the starting material, the reaction mixture wasconcentrated under reduced pressure and purified via columnchromatography (hexanes/ethyl acetate gradient) to afford the desiredring-opened DASP as white solids.

Compound 22.

DASP 22 was obtained in 95% yield. ¹H NMR (500 MHz, C₆D₆) δ 7.85-7.74(Ar, 4H), 7.28 (NH, 1H), 4.35 (dt, J=11.1, 4.3 Hz, 1H), 4.22 (dd,J=11.9, 11.9 Hz, 1H), 3.64 (dd, J=11.9, 5.1 Hz, 1H), 3.59 (dd, J=6.0,6.0 Hz, 1H), 2.09-2.04 (m, 1H), 1.98 (s, 3H), 1.93-1.68 (m, 5H),1.43-1.36 (m, 4H), 0.93 (t, J=7.7 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃) δ170.0, 165.9, 153.7, 134.5, 130.0, 123.5, 74.9, 65.1, 53.9, 53.6, 31.5,28.6, 26.2, 23.9, 22.4, 20.8, 14.0. HRMS (ESI) m/z calculated forC₂₁H₂₅N₃O₆ [M+H⁺] 416.1817, found 416.1821.

Compound 23.

¹H NMR (300 MHz, CDCl₃) δ 7.84 (m, 2H), 7.75 (m, 2H), 7.72 (br, 1H),4.06 (dd, J=9.7, 3.8 Hz, 1H), 3.93 (d, J=10.9 Hz, 1H), 3.78 (d, J=10.9Hz, 1H), 3.30, (s, 1H), 2.01 (m, 1H), 1.90 (s, 3H), 1.76 (m, 2H), 1.39(m, 5H), 1.16 (s, 3H), 1.15 (s, 3H), 0.93 (t, J=6.8 Hz, 3H). ¹³C NMR(75.5 MHz, CDCl₃) δ 169.6, 166.3, 153.4, 134.8, 129.9, 123.7, 77.6,75.3, 61.8, 54.6, 31.8, 31.2, 30.2, 26.3, 22.6, 21.6, 18.6, 14.2. HRMS(ESI) m/z calculated for [M+Na]⁺ 466.1949, found 466.1937.

Compound 24.

¹H NMR (500 MHz, CDCl₃) δ 7.84-7.73 (Ar, 4H), 7.54 (NH, 1H), 4.30 (ddd,J=11.1, 4.6, 2.3 Hz, 1H), 4.18 (ddd, J=11.7, 11.7, 2.6 Hz, 1H), 3.86(dd, J=10.7, 5.2 Hz, 1H), 3.70 (s, 1H), 2.13-2.08 (m, 1H), 1.97-1.92(overlapping signals, 4H total), 1.20 (s, 9H). ¹³C NMR (125 MHz, CDCl₃)δ 169.9, 165.9, 153.8, 134.6, 129.8, 123.5, 75.6, 64.8, 60.8, 53.7,32.1, 29.6, 28.4, 24.4, 20.9. HRMS (ESI) m/z calculated for C₂₀H₂₃N₃O₆[M+Na⁺] 424.1580, found 424.1572.

Compound 25.

¹H NMR (300 MHz, CDCl₃) δ 7.85 (m, 2H), 7.77 (m, 2H), 6.77 (s, 1H), 4.24(q, J=7.1 Hz, 2H), 3.89 (d, J=10.9 Hz, 1H), 3.81 (d, J=10.9 Hz, 1H),3.70 (dd, J=7.4, 4.6 Hz, 1H), 3.28 (d, J=0.7 Hz, 1H), 3.18 (dd, J=17.3,4.6 Hz, 1H), 2.64 (dd, J=17.3, 7.4 Hz, 1H), 2.16 (s, 3H), 1.31 (t, J=7.1Hz, 3H), 1.22 (s, 3H), 1.20 (s, 3H). ¹³C NMR (75 MHz, CDCl₃) δ 170.3,168.7, 152.6, 135.0, 130.3, 123.9, 76.3, 61.4, 61.1, 44.5, 33.1, 32.3,23.7, 21.5, 20.2, 14.4. HRMS (ESI) m/z calculated for [M+Na]⁺ 482.1534,found 482.1519.

Compound 26.

DASP 10a (0.13 mmol, 1 equiv) was dissolved in dry THF (1.5 mL) andpivalic acid (1.3 mmol, 10 equiv) was added. The reaction was stirreduntil complete by TLC (˜72 h). The reaction was quenched with asaturated solution of NaHCO₃ (15 mL) and extracted with EtOAc (3×15 mL),dried with Na₂SO₄, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (gradient 0→100% EtOAc inhexanes in increments of 20%) to give 26 in 80% yield. ¹H NMR (500 MHz,CDCl₃) δ 7.82 (s, 1H), 7.78 (m, 4H), 3.92 (d, J=10.9 Hz, 1H), 3.87 (dd,J=9.6, 3.3 Hz, 1H), 3.76 (d, J=10.9 Hz, 1H), 3.32 (s, 1H), 2.03 (m, 1H),1.78 (m, 2H), 1.42 (m, 5H), 1.19 (s, 3H), 1.13 (s, 3H), 0.93(overlapping signals, 12H). ¹³C NMR (125 MHz, CDCl₃) δ 177.0, 166.0,153.4, 134.8, 129.9, 123.6, 77.4, 75.5, 62.3, 55.1, 39.4, 31.2, 30.5,26.7, 26.4, 23.0, 22.6, 19.1, 14.2. (line broadening set at 10 toobserved the quaternary carbons). HRMS (ESI) m/z calculated for [M+Na]⁺508.2419, found 508.2413.

Compound 27.

DASP 22 (0.14 mmol, 1 equiv) was dissolved in acetone (1.4 mL) and dry,powdered LiCl (1.4 mmol, 10 equiv) was added to the reaction mixture.The suspension was stirred at rt until TLC indicated completeconsumption of 22. Water (15 mL) was added and the reaction mixtureextracted with EtOAc (3×15 mL), dried with Na₂SO₄, and concentratedunder reduced pressure. The residue was purified by silica gelchromatography (gradient 0→100% EtOAc in hexanes in increments of 20%)to give 27 in 84% yield. ¹H NMR (300 MHz, CDCl₃) δ 7.80 (m, 4H), 7.10(s, 1H), 4.41 (m, 1H), 4.26 (m, 1H), 3.71 (m, 2H), 2.22 (m, 1H), 1.99(m, 1H), 1.70 (m, 4H), 0.93 (m, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 164.0(indirectly observed by HMBC), 153.9, 134.8, 130.0 (indirectly observedby HMBC), 124.0, 71.0, 64.7, 55.1, 54.3, 31.8, 29.0, 26.5, 24.4, 22.6,14.2. HRMS (ESI) m/z calculated for [M+Na]⁺ 466.1949, found 466.1937.

Compound 28.

Chlorotrimethylsilane (150 μL, 1.18 mmol, 14 equiv) was dissolved in 1mL THF and cooled to −78° C. The DASP 10a (33.2 mg, 0.086 mmol, 1.0equiv) in 2.5 mL of THF was added dropwise over 2 min. After theaddition was complete, the reaction mixture was warmed to 0° C. for 2 hand then to room temperature for an additional 2 h. The reaction mixturewas concentrated under reduced pressure and the residue purified viacolumn chromatography (hexanes/ethyl acetate gradient) to afford 28 in93% yield as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 7.88-7.73 (Ar,4H), 7.00 (NH, 1H), 4.39 (d, J=11.2 Hz, 1H), 4.12 (dd, J=11.2, 3.9 Hz,1H), 3.74 (d, J=10.8 Hz, 1H), 3.32 (s, 1H), 2.00-1.94 (m, 1H), 1.76-1.67(m, 2H), 1.43-1.34 (m, 5H), 1.25 (s, 3H), 1.22 (s, 3H), 0.93 (t, J=6.9Hz, 3H). ¹³C NMR (125 MHz, CDCl₃) δ 166.6, 165.0, 153.2, 134.6, 130.4,129.1, 123.8, 123.3, 73.9, 70.8, 62.8, 54.2, 31.6, 31.0, 30.5, 26.5,26.4, 22.5, 20.5, 14.0. HRMS (ESI) m/z calculated for C₂₁H₂₆N₃O₄Cl[M+H⁺] 1420.1685, found 420.1666.

Compound 29.

Thioacetic acid (600 μL, 8.4 mmol, 105 equiv) was dissolved in 1.5 mL ofTHF and cooled to −78° C. The DASP 10a (30.5 mg, 0.080 mmol, 1.0 equiv)dissolved in 2.5 mL THF was added dropwise to the solution over 2 min.The reaction mixture was maintained at −78° C. for an additional 15 min,warmed to 0° C. for 2 h and then left to warm to rt overnight. After TLCindicated complete consumption of the starting materials, the volatileswere removed under reduced pressure and the crude material was purifiedvia column chromatography (hexanes/ethyl acetate gradient) to afford 29in 82% yield as an off-white solid. ¹H NMR (500 MHz, CDCl₃) δ 7.89-7.73(Ar, 4H), 7.25 (NH, 1H), 4.07 (d, J=10.5 Hz, 1H), 3.88 (dd, J=10.1, 3.8Hz, 1H), 3.80 (d, J=11.4 Hz, 1H), 3.35 (s, 1H), 2.27 (s, 3H), 2.19-2.12(m, 1H), 1.89-1.75 (m, 2H), 1.62-1.53 (m, 1H), 1.46-1.37 (m, 4H), 1.17(s, 3H), 1.14 (s, 3H), 0.94 (t, J=6.9 Hz, 3H). ¹³C NMR (125 MHz, CDCl₃)δ 193.3, 167.0, 165.1, 153.2, 134.6, 130.4, 129.3, 123.7, 123.5, 76.1,63.4, 60.9, 56.8, 31.8, 31.5, 31.2, 31.1, 26.7, 24.6, 22.5, 19.7, 14.1(line broadening set at 5 in order to observe quaternary carbons). HRMS(ESI) m/z calculated for C₂₃H₂₉N₃O₅S [M+H⁺] 1460.1901, found 460.1897.

Compound 30.

Sodium azide (0.44 mmol, 1.7 equiv) was dissolved in dry DMF (1.5 mL)and placed in an ice bath. Chlorotrimethylsilane (0.4 mmol, 1.5 equiv)was then added slowly to the solution and the reaction mixture wasstirred for 30 min. The DASP 10a (0.26 mmol, 1 equiv) was dissolved indry DMF (1 mL) and added to the reaction. The mixture was then heated to50° C. overnight (12 h) and cooled back to rt. Water (10 mL) was addedand the mixture extracted with CH₂Cl₂ (3×25 mL). The organic layer waswashed with water (3×20 mL), dried with Na₂SO₄, and concentrated underreduced pressure. The residue was purified by silica gel chromatography(gradient 0→60% EtOAc in hexanes in increments of 10%) to give 30 in 74%yield. ¹H NMR (300 MHz, CDCl₃) δ 7.89 (m, 2H), 7.76 (m, 2H), 7.21 (br,2H), 6.09 (br, 1H), 4.21 (s, 2H), 2.41 (m, 1H), 1.40 (overlappingsignals, 9H), 1.19 (m, 5H), 0.77 (m, 3H). ¹³C NMR (125 MHz, CDCl₃) δ182.7, 167.8, 159.3, 157.3, 136.8, 133.7, 126.1, 104.9, 81.9, 42.6,34.4, 33.3, 29.4, 26.5, 24.7, 16.4. HRMS (ESI) m/z calculated for[M+Na]⁺ 421.1847, found 421.1859.

Compound 31.

The DASP 10a (0.13 mmol, 1 equiv) and KCN (0.13 mmol, 1 equiv) weredissolved in dry acetonitrile (0.7 mL). Tetramethylethylenediamine(0.026 mmol, 0.2 equiv) was added to the solution, followed by TMSCN(0.16 mmol, 1.2 equiv). The reaction flask was fitted with a refluxcondenser and placed in an oil bath pre-heated to 60° C. The reactionmixture was stirred overnight (12 h) and cooled to rt. Water was added(15 mL) and the mixture extracted with EtOAc (3×15 mL), dried withNa₂SO₄, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (gradient 0→60% EtOAc in hexanesin increments of 10%) to give 31 in 48% yield. ¹H NMR (300 MHz, CDCl₃) δ8.07 (s, 1H), 7.87 (m, 2H), 7.79 (m, 2H), 4.70 (s, 1H), 4.41 (t, J=6.6Hz, 1H), 4.10 (d, J=12.1 Hz, 1H), 4.02 (d, J=12.1 Hz, 1H), 1.73 (m, 3H),1.38 (m, 5H), 1.23 (s, 3H), 1.11 (s, 3H), 0.92 (t, J=6.6 Hz, 3H). ¹³CNMR (75 MHz, CDCl₃) δ 166.2, 155.1, 145.6, 134.9, 129.9, 124.1, 117.0,101.6, 75.1, 64.1, 38.5, 32.9, 31.4, 25.5, 25.3, 24.3, 22.6, 14.1. HRMS(ESI) m/z calculated for [M+Na]⁺ 433.1847, found 433.1841.

IV. Tandem Reactions Involving 1,4-Diazaspiro[2.2]pentane Intermediates.

General Procedure for Tandem Reactions.

A 50 mL flame-dried round bottom flask was charged with 3 Å molecularsieves (500 mg), followed by Rh₂(esp)₂ (0.041 mmol, 0.025 equiv). Theallenic carbamate (1.6 mmol, 1.0 equiv) in 15 mL of dry CH₂Cl₂ was addedto the reaction flask. The resulting blue-green mixture was stirred for10 min at rt under a flow of nitrogen, then iodosobenzene (4.1 mmol, 2.5equiv) was added in one portion. The reaction was monitored by TLC untilit was complete, then cooled to 0° C. in an ice bath. A portion ofN-aminophthalimide (3.1 mmol, 1.9 equiv) and dry potassium carbonate(6.4 mmol, 4.0 equiv), followed by additional oxidant (3.0 mmol, 1.9equiv) were added and the resulting light yellow slurry allowed to warmslowly to rt. The reaction mixture was monitored by TLC and additionalportions of PhtNNH₂ and oxidant were added until no further conversionto the 1,4-diazaspiro[2.2]pentane was noted. The desired nucleophile wasthen added (3.0-15.0 equiv) and the reaction stirred at rt untilcomplete. The reaction mixture was passed through a plug of silica gelto remove solids using first Et₂O, then EtOAc to flush the plug. Thesolvents were removed under reduced pressure and the residue waspurified via silica gel column chromatography (hexanes/ethyl acetategradient). Phenyl iodide eluted first from the column, followed by theRh catalyst, unreacted methylene aziridine (if present), unreacted1,4-diazaspiro[2.2]pentane(s) (if present), products of the hydrolysisof the excess N-aminophthalimide and finally, the desired N,N-aminalproduct as a single diastereomer.

Example 3 Synthesis of 1,3-Diamines Via Allene Oxidation

Functionalized 1,3-diamines and 1,3-diamino-2-ols are valuable syntheticmotifs for the construction of biologically active compounds. Thisexample describes a one-pot bis-aziridination of allenes, followed by aLewis acid-promoted rearrangement to yield 1,3-diamino-2-ones as onemajor diastereomer. The ketone undergoes reduction to the1,3-diamino-2-ol with good diastereoselectivity.

Chiral 1,3-diamines are important building blocks for the preparation ofa variety of natural products, pharmaceutically important compounds andligands for transition metal catalysts. Approaches towards these motifsinclude the addition of enecarbamates to imines to yield anti1,3-diamines, the diastereoselective reduction of ketimines,diastereoselective C—H amination and the addition of the α-carbanion ofimines to N-protected imines, but there is still much interest indeveloping new stereoselective approaches to these molecules.

The development of new methods that can flexibly and stereoselectivelyintroduce new sp³ carbon-heteroatom bonds at the three consecutivecarbons of an allene, preferably in a single pot, is important forefficient and economical preparation of therapeutic compounds. Example 2above describes the synthesis and reactivity of an unusual class ofheterocycles, the 1,4-diazaspiro[2.2]pentanes (DASPs, Scheme 3-1, 3) viathe bis-aziridination of allenes. The reactive nature of these highlystrained intermediates, and the ability to easily obtain them inenantioenriched form, prompted exploration of the conversion of allenesdirectly to 1,3-diamino-2-ones (Scheme 3-1).

Simple hydrolysis of the N,N-aminal functionality of 3 (Scheme 3-1)should yield the 1,3-diamino-2-one 4. Attempts to transform the1,4-diazaspiro[2.2]pentane 7 (entry 1, Table 3-2) directly to the1,3-diamino-2-one 6 using a variety of Lewis acids, both in the presenceand absence of water, resulted in either no reaction or decomposition ofthe substrate. It was postulated that relieving the ring strain mightmake one of the nitrogens more accessible for binding to the Lewis acidand facilitate the desired reaction. Treatment of the ring-opened 5 witha series of Lewis and Brønsted acids (Table 3-1) was investigated tofacilitate the rearrangement of 5 to 6. Weak Lewis acids, includingCeCl₃, Ti(O^(i)Pr)₄ and ZnCl₂ (entries 1-4), gave no reaction and thestarting material was recovered unchanged. InCl₃ (entry 6) gave slowconversion to the desired product, while Cu(OTf)₂ and Sc(OTf)₃ (entries5 and 7) yielded a mixture of products. BF₃OEt₂, TsOH and Bi(OTf)₃(entries 8-12) all gave complete conversion of the starting material,with the mild Bi(OTf)₃ resulting in an 96% isolated yield of 6.

TABLE 3-1 Investigation of Lewis acids for the rearrangement.

entry additives^(a) conversion  1 CeCl₃•7H₂O  0%  2 NiCl₂•6H₂O  0%  3Ti(O^(i)Pr)₄  0%  4 ZnCl₂  0%  5 Cu(OTf)₂ 100%^(b)  6 InCl₃  33%  7Sc(OTf)₃ 100%^(b)  8 BF₃OEt₂ 100%  9 TsOH 100% 10 Bi(OTf)₃  96%^(c) 11Bi(OTf)₃ (0.2 equiv) 100% 12 Bi(OTf)₃ (0.05 equiv) 100% ^(a)1.0 equivunless otherwise indicated. ^(b)Complete conversion with several sideproducts. ^(c)Isolated yield.

Bi(OTf)₃ was chosen to further optimize the conversion of the1,4-diazaspiro[2.2]pentane 7 directly to the 1,3-diamino-2-one using acatalytic amount of the Lewis acid. Treatment of 7 with AcOH, followedby addition of the Lewis acid (Table 3-2, entry 2) gave completeconversion of the DASP, but the ring-opening with AcOH was slow.Interestingly, ring-opening with TMSCl, followed by treatment with theLewis acid (entry 3) gave only the ring-opened product and none of thedesired rearrangement. This indicates that the ester was playing animportant role in promoting the rearrangement. To significantly decreasethe reaction time, AcOH was added to 7 at 35° C. and the mixture heatedfor 8 h prior to addition of the Bi(OTf)₃ (entry 4) to give 6 in 88%isolated yield over the two steps.

TABLE 3-2 One-pot ring-opening/rearrangement of DASP.

entry conditions conversion 1 Bi(OTf)₃ (1.0 equiv)  0% 2 AcOH, thenBi(OTf)₃ (0.05 equiv)^(a) 100% 3 TMSCl, then Bi(OTf)₃ (0.05 equiv)^(b) 0% 4 AcSH, then Bi(OTf)₃ (0.05 equiv)^(b)  0% 5 ClCH₂CO₂H, thenBi(OTf)₃ (0.05 equiv) 100% 6 AcOH, then cat. TfOH 100% 7 AcOH at 35° C.,then Bi(OTf)₃ (0.05 equiv) 100% (88%)^(c,d) ^(a)40 h reaction time.^(b)The product was the ring-opened DASP. ^(c)12 h reaction time.^(d)Isolated yield with a dr >19:1.

Using relatively optimized conditions, a variety of DASPs were convertedto the corresponding 1,3-diamino-2-ones (Table 3-3). There was only aslight difference in yield between the use of the DASP 7 or thering-opened DASP 5 (entries 1-2). DASPs formed from Z bicyclic methyleneaziridines also underwent the desired rearrangement with highstereoselectivity (entries 3 and 4). The stereospecific nature of thereaction is illustrated by a comparison of the 1,3-diaminated ketone 6,obtained in 88% yield from the rearrangement of a DASP 7 derived from anE methylene aziridine, with the distinct product ketone 8c, obtained in90% yield from the rearrangement of a DASP formed from a Z-methyleneaziridine (Table 3-3, entries 2 and 4, respectively). The rearrangementwas not affected by the absence of alkyl substitution in the tether(entries 5-9) or limited to the formation of six-membered rings, as afive-membered ring-containing product (entry 8) was obtained in 78%yield. The dr of the two nitrogen-bearing stereocenters was high in mostcases (>19:1) and none of the other diastereomer was detected by ¹H NMRspectroscopy. Not surprisingly, if the product was allowed to remainunder the acidic conditions for extended periods of time, significantisomerization to a mixture of diastereomers did occur.

TABLE 3-3 Rearrangement of DASPs to 1,3-diaminated ketones.

entry^(a) R, R¹ R² E/Z^(c) n yield dr  1^(b) 5 C₅H₁₁, H Me E 1 96%6 >19:1  2 7a C₅H₁₁, H Me E 1 88% 6 >19:1  3^(b) 7b H, CH₂CO₂Et Me Z 165% 8b   86:12  4 7c H, C₅H₁₁ Me Z 1 90% 8c >19:1  5^(b) 7d C₅H₁₁, H H E1 89% 8d >19:1  6 7d C₅H₁₁, H H E 1 81% 8d >19:1  7 7e Ph(CH₂)₂, H H E 160% 8e >19:1  8^(b) 7f C₅H₁₁, H H E 0 78% 8f >19:1  9 7g ^(t)Bu, H H E 157% 8g >19:1 10 7h ^(t)Bu, H Me E 1 77% 8h >19:1 ^(a)The dr of thestarting DASPs was >19:1 in all cases. ^(b)The starting material was theacetate-opened DASP with a dr >19:1. ^(c)Stereochemistry of themethylene aziridine used to form the DASP.

One convenient advantage of this methodology arises as a result of theability to transfer the axial chirality of an enantioenriched allene tothe 1,3-diaminated products. The fidelity of this transfer was verifiedby subjecting an enantioenriched DASP to the reaction conditions for therearrangement to the ring opened product (eq 1). No degradation of theenantiopurity was indicated by chiral HPLC.

Verification was also sought for the relative stereochemistry of the twoamine-bearing stereocenters. Attempts to prepare a rigid derivative of 6were not successful. Whether the carbonyl could be reducedstereoselectively was then investigated. Obtaining X-ray crystal data onthe resulting product would then reveal the relative configuration ofthe 1,3-diamino-2-ol stereotriad. Treatment of 6 (eq. 2) with an excessof Na(OAc)₃BH gave a 70% yield of 19 as a single diastereomer, uponinitial investigation.

The conversion of an allene to the resulting 1,3-diamine can be achievedin a single pot (eq. 3). Although the yields were only moderate (ca. 80%per step), the reaction introduces significant complexity into a simple,readily available substrate. The major loss in yield occurs in the firstallene aziridination, where the formation of the Z methylene aziridine(MA) competes with that of the desired E MA. Fortunately, the Zmethylene aziridine reacts much more slowly in the subsequent reactionsand can be easily separated from the final desired product.

Interestingly, it appeared that a relatively electron-rich acetate groupwas necessary to facilitate the rearrangement. When chloride (Table 3-1,entry 3) or chloroacetic acid (entry 4) was used to open the DASP 7,reaction to the 1,3-diamino-2-one did not occur and the ring-opened DASPwas recovered unchanged. This indicates that the rearrangement may bepassing through an acetoxonium ion.

This example demonstrates that 1,4-diazaspiro[2.2]pentanes, formed viathe bis-aziridination of allenes, can serve as useful reactiveintermediates for the highly stereoselective synthesis of 1,3-diamines.The reaction also produces a ketone that can be stereoselectivelyreduced to yield 1,3-diamino-2-ols. These transformations andmethodology can be applied to the total synthesis of biologically activenatural products.

Example 4 Modular Functionalization of Allenes to Aminated Stereotriads

Nitrogen-containing stereotriads—compounds with three adjacentstereodefined carbons—are commonly found in biologically importantmolecules. However, the preparation of molecules bearing these motifscan be challenging. This example describes a modular oxidation protocolthat converts a substituted allene to a triply functionalized amine ofthe form C—X/C—N/C—Y. A key step includes a Rh-catalyzed intramolecularconversion of the allene to a strained bicyclic methylene aziridine.This reactive intermediate can be further elaborated to the targetproducts, often in one reaction vessel and with effective transfer ofthe axial chirality of the allene to point chirality in the stereotriad.

Densely functionalized amines bearing stereodefined heteroatom groupslocated adjacent to the chiral nitrogen-bearing carbon (X/N/Ystereotriads, for example, where X and Y represent a halogen, oxygen,nitrogen or sulfur-containing group) occur frequently in naturalproducts and biologically active molecules (FIG. 4). Highly modular andstreamlined methods for the chemo-, regio- and stereoselectiveconstruction of these motifs were developed as described herein. Thisexample reports the modular preparation of X/N/Y stereotriads fromallenes. These chiral hydrocarbons were chosen as precursors due totheir ease of preparation, potential for introducing three newheteroatoms in a single reaction vessel and the ability to transferreadily available axial chirality to point chirality in the products.

Allene bis-epoxidation has been the only major approach thus far tointroduce multiple heteroatoms into these chiral hydrocarbons. Previousefforts to transform allenic N-tosyloxycarbamates or carbamates 1 tobicyclic methylene aziridines 2 gave poor to moderate chemo- andstereoselectivities (Scheme 4-1, top). However, switching to an allenicsulfamate 4 gave a highly reactive methylene aziridine 5 that, in thepresence of nucleophiles, underwent regioselective ring-opening to yieldthe E-enesulfamate 6 exclusively. The cyclic nature of 6 can impart goodfacial selectivity in its subsequent reaction with an electrophile, asconformation B minimizes the A^(1,3) strain present in 6. The favoredconformation of the resulting iminium ion 7 would again minimize A^(1,3)strain. As the majority of electrophiles utilized by the inventors haveA values smaller than that of C₅H_(11,) additional shielding of the topface of 7 can result in stereoselective reduction to yield the1,2-syn:2,3-syn product 8 as the major diastereomer.

Treatment of an allenic sulfamate 9 (Table 4-1) with PhIO and catalyticRh₂TPA₄ (TPA=triphenylacetate) cleanly yielded the desired E bicyclicmethylene aziridine 5 (Scheme 4-1, R═C₅H₁₁) as observed by ¹H NMR. Aseries of weak nucleophiles promoted ring-opening of this methyleneaziridine in situ to yield the corresponding E enesulfamates. Successfuloxygen nucleophiles included AcOH, methanol and H₂O (entries 1-3) andgave the products 10-12 in good yields. The unusually activated natureof the bicyclic methylene aziridine was demonstrated by its facilereaction with amines that typically do not open aziridines in theabsence of an exogenous Lewis acid (entries 4-6). Finally, PhSH andTMSCl (entries 7, 8) were also shown to be competent nucleophiles underthese mild conditions.

TABLE 4-1 Tandem aziridination/ring-opening.

temp time prod- entry Nu—X equiv solvent^(a) (° C.) (h)^(b) yield uct1^(c) AcO—H 6 CH₂Cl₂ rt 5 75% 10 2 MeO—H 50 CH₂Cl₂ rt 1 77% 11 3 HO—H 20CH₃CN^(a) rt 0.7 74% 12 4 PhNH—H 1.3 CH₂Cl₂ rt 2 68% 13 5 morpholine 1.6CH₂Cl₂ rt 2.5 71% 14 6 piperidine 1.3 CH₂Cl₂ rt 1 75%, 15 90%^(d) 7PhS—H 10 CH₂Cl₂ rt 1 69% 16 8 Cl—TMS 1.5 THF^(a) 0° C. to rt 8 56% 17(62%)^(e) ^(a)solvent exchange ^(b)time for MA ring-opening only ^(c)0.3mol % catalyst was used ^(d1)H NMR yield based on the use of mesityleneas an internal standard ^(e)based on recovered starting material

The enesulfamates proved sufficiently nucleophilic to react with a rangeof standard electrophiles. The intermediate iminium ion 7 (see Scheme4-1) was sensitive to hydrolysis, thus, the dr of the product resultingfrom the initial nucleophilic addition step was not determined. Rather,the reductant was added to the same reaction vessel to supply the finaldesired stereotriad and the overall dr of the reaction recorded (Table4-2). For example, treatment of 10 with N-bromosuccinimide (NBS),followed by NaBH₃CN (entry 1) gave 18 in 71% isolated yield and a dr of12.5:1. The relative stereochemistry of 18 was confirmed as1,2-syn-2,3-syn by X-ray crystallography and the minor diastereomer wasassigned as 1,2-anti-2,3-syn based on ¹H NMR coupling constants. Therelative stereochemistries of the remaining products in Table 4-1 wereassigned by analogy to 18.

TABLE 4-2 Stereotriads from enesulfamates.

entry reagents product X E yield dr 1 NBS, NaBH₃CN 18 H Br 71%  12.5:1 2NCS, NaBH₃CN 19 H Cl 65%^(a)     5:1 3 TCICA, NaBH₃CN 19 H Cl 76% >19:1^(b) 4 Selectfluor ®, NaBH₃CN 20 H F 57%     2:1 5 DIAD,^(c)NaBH₃CN 21 H NN(CO₂ ^(i)Pr)₂ 69%  >19:1 6 PhSCl, NaBH₃CN 22 H SPh 80%  2.9:1^(d) 7 DMDO, STABH 23 H OH 44%     2:1^(d) 8 NBS, H—═—MgBr 24

Br 59%  >19:1 9 NBS, Me₃SiCN, cat I₂ 25 CN Br 73%   3.3:1 ^(a)NMR yieldusing mesitylene as the internal standard. ^(b)dr of the product afterpurification. ^(c)10 mol % Cu(OTf)₂ and 11 mol % Me₂N(CH₂)₂NMe₂ werealso added to the reaction. ^(d)Minor amounts of other diastereomerswere formed.

Modifying the nature of the electrophile allowed for control of the drof the stereotriad (Table 4-2, compare entries 2 and 3). WhenN-chlorosuccinimide (NCS) was employed, 19 was obtained in 65% NMR yieldand a dr of 5:1. However, the more electrophilic trichloroisocyanuricacid (TCICA, entry 3), improved both the yield and dr of 19 to 72% and>19:1.

Selectfluor® (entry 4) resulted in a 2:1 dr of 20, possibly due toincreased epimerization at C3 caused by the electron-withdrawingfluorine. The stereochemistry of the major diastereomer could beassigned by analogy to 18 as 1,2-syn:2,3-syn; however, the identity ofthe minor diastereomer was believed to be 1,2-syn:2,3-anti. Nitrogen wasintroduced at C3 using DIAD (entry 5) to provide the vicinal diaminatedstereotriad 21 in 69% yield with a dr of >19:1. PhSCl (entry 6) gave 22in 80% yield and a dr of 2.9:1, along with minor amounts of two otherstereoisomers. Reaction of 10 with DMDO (entry 7) and sodiumtriacetoxyborohydride (STABH) as the reductant gave 23 in lower dr, inthis case due to poor facial selectivity in the addition of theelectrophile to the enesulfamate. As in the case of 20, the majordiastereomer was assigned by analogy to 18 and the minor diastereomer as1,2-syn:2,3-anti by ¹H NMR coupling constants.

The challenging generation of a complex quaternary amine-bearing carbonwas accomplished by adding carbon nucleophiles to the transient iminiumion 7 according to the model proposed in Scheme 4-1. For example,employing ethynyl magnesium bromide (entry 8) in the reaction at lowtemperature gave 24 in >19:1 dr, while a Strecker-type reactionemploying TMSCN (entry 9) gave 25 in 73% yield and a dr of 3.3:1.

The allene amination chemistry was quite flexible, as demonstrated bythe conversion of a variety of heteroatom-substituted enesulfamates tothe corresponding X/N/Br stereotriads (Table 4-3). Ethers, alcohols,amines, mercaptans, and halogens were all tolerated in the reaction andgave moderate to good dr of the resulting stereotriads 26-30.

TABLE 4-3 Formation of X/N/Br stereotriads.

entry X yield crude dr isolated dr 1 11 OMe 65% 26    8:1   19:1 2 12 OH71% 27  5.6:1    4:1^(a) 3 15 piperidine 44% 28   10:1   19:1 4 16 SPh67% 29 >19:1 >19:1 5 17 Cl 77%^(b) 30 >19:1^(b) >19:1 ^(a)Afterattempted separation of the two diasteromers. ^(b1)H NMR usingmesitylene as the internal standard.

The mild reaction conditions, coupled with the high chemo-, regio- anddiastereoselectivity of the allene oxidation, allowed for conversion of9 directly to X/N/Y stereotriads in a single flask (Table 4-4). A key toobtaining high dr hinged on minimizing the time that the electrophilewas allowed to react with the intermediate enesulfamate (entries 1, 2).The 61% overall yield for the 0/N/Br stereotriad 18 (entry 2) obtainedin one pot compared favorably with the yield that was obtained when thereaction was performed in two steps (53%, Table 4-1, entry 1 and Table4-2, entry 1). When MeOH was utilized as the nucleophile (entries 3 and4), the dr of 26 was lower compared to that obtained by initiating thestereotriad formation from the isolated enesulfamate (see Table 4-3,entry 1), but the one-pot yield of 58% compared favorably with thetwo-step yield of 50%. Enantioenriched 9 (entry 5 and Scheme 4-2) gave29 in good yield and excellent dr. The use of DIAD and PhSCl as theelectrophiles with MeOH as the nucleophile (entries 5 and 6) gave 31 and32 in 64% and 74% yields, respectively, over the four consecutivereactions.

TABLE 4-4 One-pot stereotriad synthesis.

entry NuH electrophile rxn time/temp^(b) yield dr 1 AcOH NBS 2 h, rt 60%18   5:1 2 AcOH NBS 15 min, 0° C. 61% 18  20:1 3 MeOH NBS 45 min, 0° C.60% 26 1.7:1 4 MeOH NBS 10 min, −10° C. 58% 26 2.6:1 5^(c) PhSH NBS 10min, 0° C. 61% 29  15:1 6 MeOH DIAD^(d) 2 h, 70° C. 64% 31 4.6:1 7 MeOHPhSCl 30 min, rt 74% 32 2.6:1 ^(a)Conditions: 1a) 0.5 mol % Rh₂TPA₄, 1.1equiv PhIO, CH₂Cl₂, rt, 1 h, then NuH 1b) electrophile, NaBH₃CN.^(b)time and temperature for the addition of the electrophile ^(c)seeScheme 2 ^(d)Celite filtration before addition of the DIAD.

The ability to transfer the axial chirality of the allene to pointchirality in the stereotriad is an important aspect of this chemistry.As many convenient methods are available to convert enantioenrichedpropargyl alcohols to the corresponding allenes, this simplifies theformation of enantioenriched stereotriads to a diastereoselectiveprocess. As illustrated in Scheme 4-2, (R)-9 was smoothly converted into(S,S,R)-29 with no erosion in the ee.

Finally, to demonstrate that the X/N/Y stereotriads could be easilydeprotected (Scheme 4-3), the nitrogen of 32 (eq 2) was protected with aBoc group. Successive treatment of the N-protected 32 with Bu₄NCN andHCl provided 33 in 79% yield over the two steps.

Thus, a new method for the syntheses of stereotriads containing threecontiguous heteroatom-bearing carbons of the general pattern X/N/Y hasbeen developed. These transformations utilize easily prepared sulfamoylallenes and generally proceed with good chemo-, regio- anddiastereoselectivity under mild reaction conditions. The axial chiralityof an enantioenriched allene can be translated into point chirality inthe product with good fidelity. The scope of the allene, the nucleophileand the electrophile, particularly in the context of generating X/N/Cstereotriads and amines containing two or three contiguous quaternarycarbons, are described throughout the specification.

Example 5 Allene Oxidation to N- and O-Containing Stereotriads

The potency and selectivity of bioactive molecules relies on the properspatial orientation of a specific combination of functional groupstowards its intended target. Stereodefined carbon-nitrogen bonds play animportant role in determining both the binding affinity and thespecificity of certain pharmacophores. These amine groups are oftenembedded in densely functionalized arrays of three or four contiguousstereocenters (termed “stereotriads” and “stereotetrads” in thisspecification). The development of general and operationally simplemethods to prepare such motifs from readily accessible hydrocarbons isdescribed in this example.

This example describes streamlined approaches to complexheteroatom-containing stereotriads and tetrads, which are difficult toobtain using currently available synthetic methodology. The significanceand utility of these new methodologies can be demonstrated by theefficient syntheses of three important biologically active molecules:the protease inhibitor lactacystin, the anti-cancer agent(+)-pancratistatin and the antibiotic and antimalarial natural productpactamycin. The flexibility of this chemistry can enable preparation ofunique analogues of pactamycin to initiate collaborativestructure-activity relationship studies of this complexaminocyclopentitol (FIG. 5). In the various embodiments, the R, R¹, andR² of this example can each independently an optionally substituted R¹as described in the Summary and Detailed Description above.

The stereocontrolled preparation of complex amines is far from trivial,especially when the nitrogen is contained in an array of three or morecontiguous stereocenters. Typically, approaches to these motifs rely onreactions of chiral alkenes, which often results in poor regio- andstereocontrol. A method to reliably introduce multiple adjacentheteroatom-bearing chiral centers into a simple precursor in a singlereaction vessel would provide a new, unified paradigm for executing thesyntheses of complex amine arrays. Allenes are advantageous ashydrocarbon substrates because they are easily prepared from propargylalcohols in either racemic or enantioenriched form; they offer thepotential to introduce diverse combinations of three or four contiguoussp³ stereocenters in one or two simple, stereochemically predictablesynthetic manipulations; the axial chirality of an allene can betransferred to point chirality to generate diverse enantioenrichedstereotriads and tetrads without the need to employ asymmetriccatalysis; several diastereomeric stereotriads can potentially beobtained from a single allene through judicious choice of reactionconditions; and new allene oxidation methodologies can be used tostreamline the synthesis of complex bioactive molecules and theiranalogues.

A key to this innovative approach lies in employing an unexploredregio-, chemo- and stereocontrolled allene aziridination to generate ahighly reactive bicyclic methylene aziridine scaffold. The ring strainand differentiation of the hybridization of the two aziridine carbons inthis intermediate provides the thermodynamic driving force to access arange of amine-containing stereotriads with high regio- anddiastereocontrol, often in a single reaction vessel. The newmethodologies for the introduction of nitrogen into allenes can providetransformative strategies for the total synthesis of denselyfunctionalized amine motifs that occur frequently in important bioactivemolecules and natural products.

Part 1: Allene Oxidation to N- and O-Containing Stereotriads.

Stereotriads containing combinations of N- and O-bearing chiral centersare prevalent in many pharmacologically useful molecules. The range andstereochemical diversity of such motifs that can be obtained from alleneoxidation are described below.

The oxidation of chiral alkenes is among the most common ways to prepareamine-containing stereotriads (FIG. 6). While N/O/O stereotriads A arearguably the easiest targets due to lack of regiochemical issues in adihydroxylation, the synthesis of highly substituted aminodiols is stillcomplicated by reactivity and stereochemical issues. N/O/N motifs B arealso traditionally obtained through alkene oxidation. While carbonylcompounds can serve as substrates, the methods are not general. Finally,for X/N/Y and related stereotriads in C, the regiocontrol in alkeneoxidation becomes an issue, irrespective of whether a directfunctionalization approach or an indirect epoxidation/aziridination,followed by nucleophilic ring-opening, is employed.

In contrast to the use of alkenes and carbonyls for stereotriadformation, allenes as precursors have received little attention, despitethe potential for rapid access to complex amines. Much to our surprise,allene amination as a general strategy for the preparation ofstructurally complex amines had been neglected prior to the workdescribed in this example.

In terms of feasibility, the results described herein show that thestrategy to utilize allene aziridination as a key step indeed results ina range of complex amine stereotriads (Scheme 5-1).

Results. Early studies have shown that allene oxidation viaaziridination (1-1 to 1-2 in Scheme 5-1) is a remarkably flexible way toconstruct a variety of nitrogen-containing stereotriads. Successfulapproaches to motifs including N,N-aminals 1-3 (X/N/N), vicinal diamines1-4 and 1-10 (N/N/Y), 1,3-diamino-2-ols 1-5 have been devised and theirprecursors 1-6 (N/O/N) and 1-amino-2,3-diols 1-7 and 1-8 (N/O/O). Apowerful demonstration of the range of allene oxidation has been thepreparation of a series of diverse stereotriads of the form X/N/Y (1-9and 1-10, where X, Y can be O, N, S, Br, Cl or F-containingsubstituents).

Allene Oxidation to N/O/O Stereotriads.

Structurally complex and stereochemically dense N/N/O and N/O/Nstereotriads are prevalent in many bioactive compounds (FIG. 4).

Developing Predictable Stereochemical Models for Oxidizing Allenes to1,2-Anti:2,3-Syn and 1,2-Anti:2,3-Anti N/O/O Stereotriads.

The installation of three new sp³-heteroatom bearing carbons into anallene means there is a possibility of producing four diastereomericpairs of enantiomers from a single racemic substrate. Understanding thefactors that control the stereochemical outcome of allene aziridinationand subsequent transformations allow one to select for any onediastereomer through judicious choice of reaction conditions.

Preliminary studies show that allenic carbamates, such as 2-1 (Scheme5-2), undergo Rh(II)-catalyzed aziridination to yield predominantly Ebicyclic methylene aziridines, such as 2-2. Ru-catalyzed dihydroxylationof the exocyclic alkene of 2-2 is highly diastereoselective and yields1-amino-3-hydroxy-2-one 2-3 in dr>20:1. Careful reduction of 2-3 withNaBH₄ in the same pot yields the 1-amino-2,3-diol 2-4, also in >20:1 dr.The relative stereochemistry was established as 1,2-anti:2,3-syn by anX-ray crystal structure of 2-4. The high dr in 2-3 is believed to resultfrom shielding of the top face of the alkene by the carbamate ring.Removal of the gem-dimethyl groups in 2-5 and 2-6 gave only singlediastereomers (2-7 and 2-8) from the isomeric methylene aziridines. Boththe hydroxyl and the amino groups of 2-9 can react with NaBH₄, lockingthe molecule into a conformation 2-10 that favors approach of thenucleophile (hydride in this case) from the top face of the carbonyl toyield 2-11. According to this model, the identities of R and R¹ shouldnot greatly impact the stereochemical outcome.

Vicinal 1,2-Anti-2,3-Syn and 1,2-Anti-2,3-Anti QuaternaryHeteroatom-Bearing Stereocenters.

Attempts to add a series of Grignard reagents to 3-1 (Scheme 5-3,R,R¹=alkyl, aryl) resulted in a 1:1 mixture of diastereomers. The Mg²⁺ion did not appear to provide a sufficiently tight closed transitionstate to promote good stereocontrol. However, if another means to “lock”the 1,3-aminoalcohol into a rigid decalin conformation can beidentified, the addition of carbon nucleophiles to 3-2 would yieldstereotriads containing adjacent quaternary carbons similar to 3-3 inhigh dr. This can be achieved by organoboron compounds such as Bu₂BOTfor R₂BCl, organosilicons (R₂SiH₂, R₂SiCl₂) and borohydride salts of theform MB(OR)₂H₂, where M can be Li, Na or K. Nucleophiles for thegeneration of the vicinal quaternary carbon centers can include Grignardreagents, allylboranes and silanes, cyanide and enolates. Both the1,2-anti-2,3-syn and 1,2-anti-2,3-anti aminodiols can be obtainedthrough this mode of allene aziridination. Successful transformation ofa methylene aziridine such as 3-4 would yield a product 3-5 containingthree contiguous, quaternary, heteroatom-bearing chiral centers. Thehindrance imposed by an additional group at C1 should not greatly impactthe dr of the dihydroxylation of 3-4, as the top face is still moresterically congested (geometry optimized structure 3-4a).

1,2-Syn-2,3-Anti and 1,2-Syn-2,3-Syn N/O/O Stereotriads.

Stereocontrolled syntheses of the remaining two diastereomeric N/O/Ostereotriads 1,2-syn-2,3-anti 4-10 and 1,2-syn:2,3-syn 4-13 requiredifferent modes of stereocontrol in the reduction of the ketones 4-4 and4-5. Given sufficient steric differentiation between R and R¹ of 4-4,the hydroxyl group at C3 could induce chelation control to give 4-10 via4-7. This chelation can be enhanced by the addition of oxophilic Lewisacids that would bind preferentially to the O at C3 over the N at C1.Such “hard” additives, including Brønsted acids, Li⁺, Na⁺, BF₃OEt₂ andZnCl₂, can be combined with a reductant to favor generation of the1,2-syn-2,3-anti diastereomer 4-10. The use of azaphilic additives(Zn(OTf)₂, Ag⁺, Cu(OTf)₂) can favor the production of 4-6 and can beuseful if NaBH₄ fails to give good dr in more complex substrates.

The 1,2-syn:2,3-syn diastereomer 4-13 is favored when Felkin-Ahnstereocontrol involving the substituents at C3 dominates in thereduction of ketone 4-5. Installation of a bulky protecting group on theOH group, such as trityl or diphenyl-tert-butylsilyl, can serve todiscourage any competing chelation. The role the substituents on C1 playin determining the stereochemical outcome of the reduction have to bedetermined empirically by exploring the substrate scope of the bicyclicmethylene aziridines in the dihydroxylation/reduction reaction.

Another challenge in the syntheses of 1,2-anti-2,3-anti and1,2-syn-2,3-syn N/O/O stereotriads 4-9 and 4-13 is a Z-selective alleneaziridination catalyst. Rh₂(OAc)₄ yields significant amounts of the Zmethylene aziridine (ca. 50%). As an alternative approach, the Ebicyclic methylene aziridine 5-2 can be epoxidized to the reactive 5-3with high facial selectivity (Scheme 5-5). Selective ring-opening at C3can give ketone 5-4, effectively inverting the stereochemistry at C3.The appropriate reduction can then yield either the 1,2-anti:2,3-anti5-5 by the model of 2-10 or the 1,2-syn:2,3-syn 5-6 from Felkin-Ahncontrol by C3.

Allene Oxidation to N/O/N Stereotriads.

Bicyclic methylene aziridines undergo regioselective aminohydroxylation,followed by reduction, to yield 1,3-diamino-2-ol motifs valuable for theconstruction of cholesterol-lowering statins, antibiotic aminoglycosidesand protease inhibitors (FIG. 4). Both 6-2 and 6-4 (Scheme 5-6) weresmoothly transformed into the 1,3-diamino-2-ols 6-3 and 6-5 with highregio- and diastereoselectivity. In contrast to the dihydroxylation ofbicyclic methylene aziridines, removal of the gem dimethyl groups in 6-6decreased the dr in the reduction of the ketone to 1.7:1 in 6-7. Theelectron-withdrawing sulfonamide group at C3 may make binding both the Nand the O to NaBH₄ slower than the background reduction. Pre-formationof a diazaborolidine or a structure similar to 6-9 can improvestereocontrol in the reduction of 1,3-aminohydroxy-2-ones with bothhydrides and carbon nucleophiles.

Allene Oxidation to N/N/O and N/N/N Stereotriads.

The flexibility of allene oxidation can be further extended to includethe preparation of N/N/N and N/N/O stereotriads from the1,3-diamino-2-one 7-1 and 1-amino-3-hydroxy-2-one 7-2 intermediates thatarise from aminohydroxylation and dihydroxylation of bicyclic methyleneaziridines, respectively (Schemes 5-2 and 5-6). The stereochemicalmodels developed for the ketone reduction can be applicable to reductiveamination (7-3). This can provide the 1,2-anti:2,3-syn triamines 7-4 andthe 1,2-anti:2,3-syn diamino alcohols 7-5 (Scheme 5-7).

Thus, this example describes the ability to prepare complexnitrogen-containing synthetic motifs (N/O/O, N/O/N, N/N/O and N/N/Nstereotriads) in a rapid and stereocontrolled fashion from allenes, anddescribes the general reactivity of bicyclic methylene aziridinescaffolds.

Part 2: Flexible Preparation of More Diverse Stereotriads and Tetradsfrom Allenes and Applications to the Synthesis of Lactacystin and(+)-Pancratistatin.

The analysis below describes the expansion of the range andstereochemical diversity of the motifs that can be obtained using thekey allene aziridination strategy, focusing on the nucleophilicring-openings of bicyclic methylene aziridines and their subsequenttransformations to X/N/Y and C/N/Y stereotriads and related X/N/C/Ystereotetrads.

Numerous important natural products contain complex amine stereotriadsof an X/N/Y or C/N/Y pattern, where X and Y is, for example, a N, O, Sor halogen group (FIG. 4). In Part 1 above, the reactions focused on thedouble bond of a bicyclic methylene aziridine resulting from alleneaziridination to provide N/O/O, N/O/N, N/N/O and N/N/N stereotriads.That approach was amenable for introducing O and N heteroatoms. Thispart describes nucleophilic ring-opening of methylene aziridines,followed by reaction of the resulting enamines, to introduce diverseheteroatoms into stereotriads.

Results.

The strategy of Scheme 5-8 was very successful and contains threedifferent points in the synthetic sequence (8-2, 8-3, 8-4) wherediversity can be introduced into the stereotriad. Other key results areshown in Scheme 5-9. As shown in eq 1, 9-1 can be converted to the X/N/Ystereotriad 9-2 in a single reaction vessel with good yield andexcellent dr. The ability to deprotect the stereotriads is alsoimportant and eq 2 illustrates one of several ways to achieve thisresult. Finally, the ability to transfer the axial chirality of (R)-9-1to point chirality in (S,S,R)-9-5 with excellent fidelity was verified.

Allene Oxidation to X/N/Y Stereotriads. Developing PredictableStereochemical Models for 1,2-Syn:2,3-Syn and 1,2-Anti:2,3-Anti X/N/YStereotriads.

Allenes can be transformed to a variety of X/N/Y stereotriads using theapproach shown in Scheme 5-8. Interestingly, the major product containedthe 1,2-syn:2,3-syn stereochemistry. This understanding of the factorscontrolling this stereochemical outcome allows access to the other threepossible diastereomers of a given stereotriad.

The preference for the 1,2-syn-2,3-syn isomer 10-2 (Scheme 5-10) isconsistent with A undergoing a conformational change to relieve A^(1,3)strain. This places the Nu above the plane of the alkene, prompting theelectrophile to approach from the more accessible bottom face, yieldingB. Attack of the final nucleophile from the bottom face of the iminiumion then results in the observed 1,2-syn:2,3-syn 10-2. If the1,2-anti-2,3-anti isomer 10-4 is desired, substrate control in thereduction step must be overridden. This can be accomplished through adirected, intramolecular delivery of the hydride to the iminium ionusing an adjacent hydroxyl or amine group. Suitable reductants caninclude Red-Al, (RO)₂BH₂ and LiBH₄.

Preparation of 1,2-Syn-2,3-Anti and 1,2-Anti-2,3-Syn X/N/Y Stereotriads.

A straightforward approach to the remaining 1,2-syn:2,3-anti and1,2-anti:2,3-syn diastereomers 11-7 and 11-9 can be achieved byaccessing the bicyclic methylene aziridine 11-2. The E enesulfamate 11-1can be isomerized to the Z enesulfamate 11-2 usingN-iodosuccinimide/NaBH₃CN via 11-4. According to the stereochemicalmodel outlined in Scheme 5-10, the lack of significant A^(1,3) strain in11-3 can allow the electrophile to approach from either the top orbottom face of the enesulfamate, leading to both 11-5a and 11-5b. Themodel also predicts that relief of A^(1,3) strain in the iminium ionintermediates 11-5a and 11-5b can promote reduction from the bottom facein both cases, leading to the all syn product 10-2 (Scheme 5-10) and thedesired 1,2-syn-2,3-anti product 11-7. Additional substitution in thetether between the allene and the sulfamate to discourage approach ofelectrophiles from the top face of the alkene can provide good dr in thereactions of Z-enesulfamates. Also, 1,3,3-trisubstituted allenes can besuccessful substrates because they provide the necessary A^(1,3) strainin 11-3 for good dr.

Obtaining the 1,2-anti:2,3-syn diastereomer 11-9 from the Z-enesulfamateis challenging because substrate control in both the electrophilicaddition and reduction steps must be substantially overridden. Thus, analternative approach can be more suitable (Scheme 5-12) in certaincircumstances. Treatment of a Nu/N/Br stereotriad 12-1 (easily obtainedas shown in Scheme 5-8) with a base can form an intermediate aziridine12-2. Depending on the substitution pattern of 12-2, it can be openedwith a nucleophile at C2 to yield the desired 1,2-anti:2,3-syn product12-4 or at C3 to give the all syn 12-6. In the latter case, this permitsthe introduction of diverse heteroatoms at C3 using a nucleophileinstead of an electrophile. Finally, direct S_(N)2 displacement of asecondary halide in 12-1 can be used for the synthesis of1,2-syn:2,3-anti isomers 12-5. These reactions provide a series ofpredictable and selective methods to secure any one of the four possiblediastereomers for a given stereotriad.

Expansion of the Scope of Heteroatom-Containing Nucleophiles andElectrophiles for the Synthesis of X/N/Y Stereotriads.

As illustrated in Scheme 5-8, there are three points of diversity in theapproach to the preparation of X/N/Y stereotriads from allenes. Abroader range of nucleophiles for the ring-opening of the bicyclicmethylene aziridine, including F, Cl, Br, CF₃ and P-based anions andthose based on O, N containing easily unmasked protecting groups can beused. Additional electrophilic sources of F, Cl, Br, I, N, O, S and Pand other nucleophiles for addition to the iminium ion intermediate canalso be used (e.g., Grignard and organozinc reagents, cyanide,allylsilanes and boranes, enolates, enamines). Current results (Scheme5-9, eq 1) show that allene oxidation to form the X/N/Y stereotriad canbe carried out in a single pot.

Total Synthesis of Lactacystin.

The proteolytic degradation of cellular proteins is a crucial biologicalprocess. In particular, the breakdown of ubiquitinated proteins by the20S proteasome plays a key role in regulating transcription factors andcell division. Diseases, including cancer and neurodegenerativedisorders, can arise from malfunctions in the ubiquitin-proteasomesystem. As a result, proteasome inhibitors have received intenseinterest from the synthetic community. Lactacystin was the first natural20S proteasome inhibitor to be identified and was isolated from theStreptomyces sp. in 1991. This “touchstone” molecule, for which severalsyntheses have been reported, would be suitable for a quickdemonstration of the utility of allene aziridination in total synthesisprior to pursuing other targets.

The retrosynthesis shown in Scheme 5-13 installs the thioester sidechain of lactacystin 13-1 as the penultimate step, a transformation thatis well-precedented. The γ-lactam core of 13-1 arises from aRu-catalyzed oxidation of a pyrrolidine 13-2. This heterocycle can begenerated via a NaI-mediated ring-opening of the sulfamate 13-3,followed by intramolecular cyclization to the pyrrolidine. The sulfamate13-3 can be accessible in a single pot from the enantioenriched allene13-4, based on the precedent established in the inventors' earlierstudies.

The forward synthesis can begin with allene 14-1 (Scheme 5-14), formedin four steps from an alkynyl ketone. Compound 14-1 can be subjected toaziridination and can yield 14-2a as a single stereoisomer. Ring-openingwith AcOH, followed by treatment with DMDO can result in an iminium ion14-2c, which can engage in a modified Strecker reaction to give 14-3.Results suggest the dr of 14-3 should be at least 3:1 (see Scheme 5-8),but increasing the electrophilicity of the dioxirane can improve theselectivity. Standard protections, followed by precedented ring-openingof the cyclic sulfamate with NaI and triggering of ring-closure withNaH, can lead to the pyrrolidine 14-4. Reaction of 14-4 with Red-Alreduces the nitrile to an aldehyde and removes the acetate protectinggroup from the hydroxyl group at C1. Subsequent treatment with catalyticRuCl₃ in the presence of an oxidant can accomplish four transformationsin a single pot: the precedented conversion of the pyrrolidine to thelactam and oxidations of the benzyl to a benzoate, the alcohol to aketone and the aldehyde to a carboxylic acid to give 14-5.

The final sequence of steps involves substrate-controlled reduction ofthe ketone and deprotection to 14-6, followed by well-precedentedtransformations to the target lactacystin. The overall sequence can becarried out in 11 steps from the key allene substrate 14-1 and 15 stepsfrom an inexpensive commercial starting material. In addition to beingshorter than most existing syntheses, the approach uses an inherentlymore flexible strategy that does not rely on substrates from the chiralpool.

An alternative strategy can be invoked if the use of DMDO as theelectrophile leads to low dr in the allene oxidation (Scheme 5-15).Installation of a Br at C3, which occurs in dr>20:1, can provide 15-1.Treatment of this stereotriad with NaH can trigger formation of theaziridine 15-2, which can be opened with BnOH in a double displacementreaction to retain the original stereochemistry at C3 of 15-3. A similartransformation using MeOH as the nucleophile provided an OAc/N/Brstereotriad in 10:1 dr with retention of the C3 stereochemistry.

Allene oxidation to C/N/Y and X/N/C stereotriads and tetrads. Thus far,the reactions have focused on methods to install diverse heteroatoms ateach of the three carbons of an allene. The ability to introduce new C—Cbonds at both C1 and C3 of the allene greatly expands the scope andutility of allene oxidation.

Carbon-Based Nucleophiles for the Ring-Opening of Bicyclic MethyleneAziridines: Synthesis of C/N/Y Stereotriads and Tetrads.

The ring-opening of typical aziridines with weak carbon nucleophiles(electron-rich aromatics, malonates, enolates and enamines) can bedifficult and the substrate scope is generally limited to terminaland/or phenyl-substituted aziridines. However, the additional strainpresent in a bicyclic methylene aziridine (˜42 kcal/mol compared to 27kcal/mol for a typical aziridine) has enabled the opening of these ringswith weak nucleophiles such as malonate anions, an exciting indicationof the potential of allene oxidation methods in the formation ofstereodefined C—C bonds.

Carbon nucleophiles can lead to useful motifs for total syntheses(Scheme 5-16). This includes indoles en route to the preparation ofhexahydropyrrolo[2,3-b]indoles via 16-2, electron-rich benzenes for thesynthesis of (+)-pancratistatin, enolates and enamines leading tostereotetrads of the form 16-3, and acyl anion equivalents that canyield unnatural amino acids or 1,3-diamine motifs from 16-4 and 16-5.

X/N/C/N and X/N/C/O Stereotetrads Using Electrophilic Carbon Species.

Enesulfamates 17-1 and enecarbamates are produced by ring-opening ofmethylene aziridines. Reaction of these nucleophilic species with carbonelectrophiles can offer access to aminated stereotetrads in high dr. Anopen transition state (Scheme 5-17) can provide access to all 8 possiblediastereomeric stereotetrads, depending on the geometry of 17-1 or 17-7(which can be controlled; see Schemes 5-10 and 5-11), the identity ofthe Lewis acid, and the conditions used to reduce the intermediateimines 17-3 and 17-5. These studies provide valuable information aboutstereocontrol in the reactions of cyclic enecarbamates and sulfamateswith aldehydes and other carbon-based electrophiles, includingimines/iminium ions, Michael acceptors and oxonium ions.

Total Synthesis of (+)-Pancratistatin.

Pancratistatin was isolated in 1984 from the bulbs of the Hawaiianflower Hymenocallis littoralis. It has received intense interest due toits strong in vivo activity against cancer cell growth, as well as itspotent antiviral and antiparasitic properties. Unfortunately, minimalquantities of the material can be obtained from the natural source andno synthetic route to date has been of sufficient simplicity to allowfor the preparation of useful amounts of material. A synthetic sequenceto (+)-pancratistatin using allene oxidation as a key step to form thestereotriad outlined is shown in Scheme 5-18. The lactam of 18-1 can beformed from a precedented modified Bischler-Naperialski reaction of aprecursor similar to 18-2, while the carbocycle of 18-2 can arise from aring-closing metathesis. The bis-alkene employed for the RCM reactioncan arise from functional group manipulations of 18-3. Cyclic sulfamate18-3 can result from the application of our methodology to oxidation ofthe enantioenriched allene 18-4, using an electron-rich aromatic as thenucleophile to open the key bicyclic methylene aziridine intermediate.

In the forward synthesis (Scheme 5-19), 19-1 can be prepared in threesteps from a chiral propargyl alcohol. Application of the methodologydescribed herein to 19-1 using 19-2 as the nucleophile yields 19-3. Ifregiocontrol in the addition of 19-2 to the bicyclic methylene aziridineproves problematic, steric and/or electronic manipulation of theprotecting groups on the aromatic ring can be explored to favor thedesired isomer of 19-3. Straightforward transformations can provide 19-6for the ring-closing metathesis to the cyclohexene. There is literatureprecedent to support the ring-closure of a doubly allylic diene using avariety of Grubbs' catalysts. Diastereoselective epoxidation andHClO₄-mediated intramolecular ring-opening by the carbamate oxygen cansupply 19-7. The penultimate step can be a modified Bischler-Napieralskicyclization to the lactam via an isocyanate intermediate. Regioisomericmixtures from attack by either b or c may result, but literatureprecedent indicates a more electron-donating protecting group at thephenol a will favor production of the desired regioisomer 19-8. A globaldeprotection reveals (+)-pancratistatin.

The work described in Part 2 significantly expand the scope of alleneoxidation via tunable and stereocontrolled methods to produce diversestereotriads and tetrads. The utility of these methods can be showcasedin total syntheses of lactacystin and (+)-pancratistatin.

Part 3: Application of Allene Oxidation to the Synthesis of Pactamycinand Novel Analogues.

In this section, the flexibility of the methods is demonstrated by thedescription of a formal synthesis of pactamycin and novel analogues toempower structure-activity studies of this potent anti-malarial andantibiotic compound.

There is a continuing need for increasingly efficient methods to preparebioactive natural products and analogues exhibiting improved activityand specificity. Pactamycin (FIG. 4), the most densely functionalizedaminocyclopentitol natural product known, is an excellent target todemonstrate the modularity and flexibility of the new methodologiesdescribed herein. The molecule is a potent protease inhibitor andexhibits anti-cancer, antibiotic and anti-malarial activities. However,its synthetic complexity has prevented SAR studies. Recently, geneticengineering has yielded two simple analogues of pactamycin that shownanomolar activity against chloroquine-resistant strains of Plasmodiumfalciparum and a 30-fold decrease in toxicity towards mammalian cells,compared to the parent compound. This report spurs interest in applyingan allene oxidation approach to the synthesis of pactamycin andanalogues. The stereochemistry and the identity of the heteroatoms canbe manipulated with only minor changes to the overall syntheticstrategy.

Formal Total Synthesis of Pactamycin.

Even though the structure of pactamycin was determined over 50 yearsago, there has been only one total synthesis reported to date. TheHanessian group accomplished the synthesis of pactamycin in 32 stepsfrom L-threonine (Angew. Chem. Int. Ed. 2011, 50, 3497). Alleneoxidation methodology can provide rapid access to the stereochemicallydense core of pactamycin in far fewer synthetic steps and with increasedflexibility for the preparation of analogues.

There are several amine-containing stereotriads present in pactamycinthat can be obtained through our allene oxidation (Scheme 5-20), butthis example focuses efforts on construction of the N/N/O stereotriad atC2/C1/C7 of the molecule. The retrosynthesis in Scheme 5-21 describesthe approach to 20-1, which differs from an intermediate reported byHanessian only in the presence of a primary amine at C2 instead of anazide. This compound is proposed to arise from an intramolecularpinacol-type coupling of 20-2. The substrate for the coupling can beobtained from 20-3, the expected product of the application of theoxidation protocol to 20-4.

In the forward synthesis, 21-1 (Scheme 5-22) can be subjected to alleneoxidation to yield 21-2. Compound 21-1 can be prepared by minormodifications to a route reported by Krause and co-workers (Tetrahedron2004, 60, 11671). Treatment of 12-2 with p-anisoyl chloride, followed bydeprotection of the sulfamate, can unmask the amino alcohol and triggercyclization of the amide carbonyl onto the secondary Br at C7. Thistransformation can serve to both invert the stereochemistry at C7 andprotect the C1/C7 aminoalcohol as the oxazoline 21-3. Careful oxidationof the terminal alcohol to an aldehyde, addition of Bu₃SnCHLiOTBS andoxidation of the resulting alcohol can give ketone 21-4. If the stericcongestion of the nitrile is not sufficient to prevent its reaction withthe organometallic reagent, a milder nucleophile, such as an organozinc,can be employed.

Intramolecular pinacol couplings of congested ketoaldehydes arewell-precedented, as well as the use of a nitrile as one of theunsaturated coupling partners. SmI₂ is the mildest and most commonlyemployed one-electron reductant, although TiI₄, Cp₂VCl₂/Me₃SiCl/Zn, andMg have also been utilized. Diastereocontrol in the reaction of 21-4 canbe impacted by the specific reaction conditions, but the largecoordination sphere of SmI₂ can lead to preferential two-point bindingon the top face of 21-5 to yield the desired 21-5a. However, evendiastereomer 21-5b can yield valuable SAR data. Because employing anitrile in the pinacol-type coupling directly installs a ketone at C5,addition of MeMgBr to the top face of the carbonyl can be followed byremoval of the TBS group to yield 21-6. The final two reactions areclosely based on Hanessian's work and result in cleavage of both theoxazoline and the Boc groups, as well as the installation of anacetonide group on the primary and secondary vicinal alcohols. Thepreparation of 20-1 essentially represents a formal total synthesis ofpactamycin (the primary C2 amine can be converted to an azide bytreatment with TfN₃), but more importantly, provides an approach thatcan be easily modified to prepare novel analogues. Preparation ofHanessian's key intermediate required 26 steps, while this route standsat 10 steps. Even if a few extra functional group interconversions orprotections need to be invoked, this route is significantly shorter.

Synthesis of Novel Analogues of Pactamycin.

Genetic engineering has resulted in two simplified analogues ofpactamycin with potent anti-malarial activity and significantlydecreased toxicity towards mammalian cells (Scheme 5-23, a=Me and a=Me,b=H). However, modifications in the identity and stereochemistry of thevarious heteroatoms require a synthetic approach. This provides anexcellent opportunity to harness the flexibility of the allene oxidationmethodology to prepare a small library of analogues. Amine groups areknown to play an important role in both binding and specificity, thus,an initial library of analogues can probe the effect of the amines at C2and C3, as well as the hydroxyl group located at C7 on the activity ofthe molecule. The amine at C3 comprises R² of the substrate 22-1 and canbe easily modified during the allene synthesis. This C—N bond can bereplaced with both C—O and C—C bonds to determine the effect on thebinding affinity and toxicity profile of pactamycin, while the use ofdifferent Nu and E in the allene oxidation sequence (Scheme 5-22) canresult in modification of the groups at C7 and C2.

This example showcases allene oxidation as valuable tools for the totalsynthesis of the structurally dense and complex aminocyclopentitolnatural product, pactamycin. The flexibility of this methodology enablesanalogue synthesis to aid efforts to understand how the identity andchirality of individual heteroatoms in pactamycin's core structureaffect its binding specificity to mammalian vs. bacterial RNA.

In summary, this example provides a solution to the long-standingchallenge of synthesizing stereochemically complex amines that occur inmany important biologically active molecules. A suite of transformativeallene oxidation methods that provide new paradigms for the constructionof enantioenriched nitrogenated stereotriads and tetrads is described.These methods are remarkably flexible and permit access to severaldiastereomeric N/O/O, N/O/N, N/N/O, N/N/N, X/N/Y, C/N/Y, X/N/C/N andX/N/C/O stereotriads and tetrads from a single allene precursor. All ofthese new methods take advantage of the axial chirality of the allenesubstrate, enabling the synthesis of enantioenriched stereotriadscontaining a variety of carbon-carbon and carbon-heteroatom bondswithout having to employ any asymmetric catalysis. Three examples,(+)-lactacystin, (+)-pancratistatin and pactamycin, are used to describehow allene oxidation can be applied in total synthesis to streamline thepreparation of complex amine-containing natural products.

While specific embodiments have been described above with reference tothe disclosed embodiments and examples, such embodiments are onlyillustrative and do not limit the scope of the invention. Changes andmodifications can be made in accordance with ordinary skill in the artwithout departing from the invention in its broader aspects as definedin the following claims.

All publications, patents, and patent documents are incorporated byreference herein, as though individually incorporated by reference. Theinvention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

What is claimed is:
 1. A method comprising forming a bicyclic methyleneaziridine by an intramolecular allene aziridination reaction; wherein anallene group is tethered to an —NH₂ group, and the amino group isseparated from the proximal allene carbon by 3, 4, 5, or 6 atomslinearly; the method comprising combining the allene, an effectiverhodium catalyst, a solvent, and an oxidant, to provide a reactionmixture, thereby initiating an intramolecular allene aziridinationreaction, to provide a bicyclic methylene aziridine.
 2. The method ofclaim 1 wherein the rhodium catalyst is Rh₂(esp)₂ where esp isα,α,α′,α′-tetramethyl-1,3-benzenedipropionate, or Rh₂(TPA)₄ where TPA istriphenylacetate.
 3. The method of claim 2 wherein the oxidant is ahypervalent iodide oxidant or a one-electron cerium or lead oxidant. 4.The method of claim 3 wherein the oxidant is PhIO, PhI(OAc)₂,PhI(OPiv)₂, Ce₂(SO₄)₃, or Pb(OAc)₄.
 5. The method of claim 4 wherein thereaction mixture further comprises a drying agent, an acid neutralizingagent, or a combination thereof.
 6. The method claim 1 wherein theaziridine nitrogen of the bicyclic methylene aziridine is substituted byan electron-withdrawing group.
 7. The method of claim 1 wherein theallene is mono-substituted, di-substituted, tri-substituted, ortetra-substituted.
 8. The method of claim 1 wherein the allene is acompound of Formula I:

wherein R¹, R², and R³ are each independently H, alkyl, cycloalkyl,aryl, heteroaryl, heterocycle, (alkyl)cycloalkyl, (alkyl)aryl,(alkyl)heteroaryl, or (alkyl)heterocycle; n is 1, 2, or 3; Y is —C(═O)—or —S(═O)₂—; and each Z is independently —(CH₂)—, —(CHR¹)—, or—(C(R¹)₂)—.
 9. The method of claim 8 further comprising contacting thebicyclic methylene aziridine with a nucleophile to provide anucleophile-addition product.
 10. The method of claim 9 wherein thenucleophile-addition product is an enecarbamate or an enesulphone. 11.The method of claim 9 wherein the nucleophile comprises a carboxylicacid, a halide, an alcohol in the presence of an acid, a thiol in thepresence of an acid, a cyanide, an azide, a malonate, or an alkylmagnesium nucleophile.
 12. The method of claim 8 wherein the bicyclicmethylene aziridine is a compound of Formula II:

wherein R¹ and R² are each independently H, alkyl, cycloalkyl, aryl,heteroaryl, heterocycle, (alkyl)cycloalkyl, (alkyl)aryl,(alkyl)heteroaryl, or (alkyl)heterocycle; n is 0, 1, or 2; Y is —C(═O)—or —S(═O)₂—; and each Z is independently —(CH₂)—, —(CHR¹)—, or—(C(R¹)₂)—.
 13. The method of claim 12 wherein the nucleophile-additionproduct is a compound of Formula III:

wherein R¹ and R² are each independently H, alkyl, cycloalkyl, aryl,heteroaryl, heterocycle, (alkyl)cycloalkyl, (alkyl)aryl,(alkyl)heteroaryl, (alkyl)heterocycle, or azide; n is 0 or 1; the dottedlines represent optional double bonds where only one of the double bondsis present; Y is —C(═O)— or —S(═O)₂—; and R^(N) is acetoxy,chloroacetoxy, halo, cyano, hydroxy, alkoxy, thioalkyl, or thioaryl. 14.The method of claim 13 further comprising reacting thenucleophile-addition product with an electrophile to provide anelectrophile-addition product.
 15. The method of claim 14 furthercomprising reducing the electrophile-addition product to provide asynthetic motif containing three contiguous carbon-heteroatom bonds. 16.The method of claim 13 further comprising contacting thenucleophile-addition product with a nitrene equivalent in the presenceof an oxidant to provide an N,N-spiroaminal.
 17. The method of claim 16wherein the N,N-spiroaminal has four contiguous carbon-heteroatom bondsin the form of a tricyclic 1,4-diazaspiro[2.2]pentane (DASP).
 19. Themethod of claim 17 further comprising contacting the DASP and anucleophile to provide a bicyclic ring opened nucleophile-additionproduct.
 20. A method comprising forming a bicyclic an N,N-aminal, themethod comprising forming a bicyclic methylene aziridine by anintramolecular allene aziridination reaction; wherein an allene group istethered to an —NH₂ group, and the amino group is separated from theproximal allene carbon by 3, 4, 5, or 6 atoms linearly; the methodcomprising combining the allene, a rhodium catalyst, a solvent, and anoxidant, to provide a reaction mixture, thereby initiating anintramolecular allene aziridination reaction, to provide a bicyclicmethylene aziridine; contacting the bicyclic methylene aziridine with anitrene equivalent in the presence of an oxidant to provide anN,N-spiroaminal; and contacting the N,N-spiroaminal with a nucleophileto provide a bicyclic ring opened nucleophile-addition product.
 21. Themethod of claim 20 wherein the reaction is carried out as a one-potreaction.